PubMed tietoa ihmiseen tarttuneista H7N9 - infektioista

https://www.ncbi.nlm.nih.gov/pubmed/30572825

BMC Infect Dis. 2018 Dec 20;18(1):685. doi: 10.1186/s12879-018-3592-9. Muscle weakness associated with H7N9 infection: report of two cases.

Jin CN¹, Tang LL². Abstract   BACKGROUND:

The emerging avian influenza A (H7N9) virus, a subtype of influenza viruses, was first discovered in March 2013 in China. Infected patients frequently present with pneumonia and acute respiratory disorder syndrome with high rates of intensive care unit admission and death. Neurological complications, such as Guillain-Barré syndrome(GBS), and intensive care unit-acquired weakness, including critical illness polyneuropathy and myopathy, have only rarely been reported previously.  CASE PRESENTATION:
In this study, we report on two Chinese patients with H7N9 severe pneumonia presenting neurological complications. These two patients had non-immune diseases prior to the onset of virus infection. A 56-year-old female patient (case 1) and a 78-year-old female patient (case 2) were admitted because of fever, cough, chest tightness and shortness of breath. These patients were confirmed to have H7N9 infection soon after admission followed by the development of acute respiratory distress syndrome and various severe bacterial and fungal infections. The case 1 patient was found to have muscle weakness in all extremities after withdrawing the mechanical ventilator, and the case 2 patient was found when withdrawing extracorporeal membrane oxygenation, both of these conditions prolonged ventilator-weaning time. Furthermore, the case 1 patient carried the H7N9 virus for a prolonged period, reaching 28 days, and both of them stayed in the hospital for more than two months. A clinical diagnosis of intensive care unit-acquired weakness could be confirmed. However, based on results from electrophysiological testing and needle electromyography of these 2 patients, it is difficult to differentiate critical illness polyneuropathy from GBS, since no lumbar puncture or muscle and nerve biopsy were conducted during hospitalization. Following a long-term comprehensive treatment, the patients' neurological condition improved gradually. CONCLUSIONS: Although there is great improvement in saving severe patients' lives from fatal respiratory and blood infections, it is necessary to pay sufficient attention and to use more methods to differentiate GBS from intensive care unit-acquired weakness. This unusual neurological complication could result in additional complications including ventilator associated pneumonia, prolonged hospital stay and then would further increase the death rate, and huge costs.

https://www.ncbi.nlm.nih.gov/pubmed/30680746

J Med Virol. 2019 Jan 24. doi: 10.1002/jmv.25408. [Epub ahead of print]

Establishment of sandwich ELISA for detecting the H7 subtype influenza A virus.

Chen L^1,2,3, Ruan F^1,2,3, Sun Y², Chen H³, Liu M³, Zhou J², Qin K².  Abstract

Avian H7N9 subtype influenza virus infects human with high case-fatality rate since it emerged in 2013. Although the vaccination has been rapidly used in poultry due to the emergence of highly pathogenic strain, this virus remains prevalent in this region. Thus, rapid diagnosis both in poultry and human clinic is critically important for the control and prevention of H7N9 infection. In this study, a batch of H7 subtype-specific monoclonal antibodies (mAbs) were developed and a pair of mAb, 2B6, and 5E9 were used to establish a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) to quantify H7 protein and detect influenza A virus baring H7 subtype HA. The lowest detection limit for the recombinant H7 protein was 10 ng/mL and 0.5 HAU/50 μL of A/Guangdong/17SF003/2016(H7N9), 2 HAU/50 μL of A/Netherlands/219/2003(H7N7) and A/Anhui/1/2013(H7N9) for live virus, respectively. The ELISA could not only detect the prevailing H7N9 virus, but also antigenic drift H7 subtype viruses, showing excellent sensitivity and high specificity. Hence, it could serve as a valuable approach to diagnose H7 subtype virus which showed great potential to cause pandemic, as well as antigen quantification.

© 2019 Wiley Periodicals, Inc.

https://www.ncbi.nlm.nih.gov/pubmed/30592958 

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2018 Dec;30(12):1200-1201. doi: 10.3760/cma.j.issn.2095-4352.2018.012.019.

[The first case of severe avian influenza A (H7N9) in Guangdong Province in 2018 successfully treated with extracorporeal membrane oxygenation].

[Article in Chinese] Li J¹, Jiang H, Li B, Liang H, Wu G, Xu X, Hou L, Chen M, Ruan Z Abstract

Human infection with avian influenza A (H7N9) is easy to induce severe acute respiratory distress syndrome (ARDS), and traditional mechanical ventilation cannot correct hypoxemia, so patients may die from multiple organ failure (MOF) caused by persistent hypoxia. Extracorporeal membrane oxygenation (ECMO) can provide effective respiratory support and win time for the treatment of severe H7N9. The first case of severe H7N9 in Guangdong Province in 2018 was admitted to Zhongshan Hospital Affiliated to Sun Yat-sen University. The case was insult with severe ARDS caused by H7N9, the traditional mechanical ventilation could not correct hypoxemia, and the lung condition gradually improved with ECMO assistance. After 13 days of ECMO support, the patient was successfully weaned from ECMO and was transferred to a general ward after 55 days. After 102 days of rehabilitation, the patient was discharged from hospital and followed up for 2 months, who was in good health and had a good quality of life. This article states the diagnosis and treatment of severe H7N9 in details, providing experience for the treatment of severe H7N9 in the future.

https://www.ncbi.nlm.nih.gov/pubmed/30551738

Clinical, immunological and bacteriological characteristics of H7N9 patients nosocomially co-infected by Acinetobacter Baumannii: a case control study.

Liu WJ^1,2, Zou R¹, Hu Y³, Zhao M³, Quan C², Tan S³, Luo K¹, Yuan J¹, Zheng H¹, Liu J⁴, Liu M⁴, Bi Y^1,3,5, Yan J³, Zhu B³, Wang D², Wu G², Liu L¹, Yuen KY⁶, Gao GF^7,8,9,10, Liu Y¹¹.Abstract BACKGROUND: Bacterial co-infection of patients suffering from influenza pneumonia is a key element that increases morbidity and mortality. The occurrence of Acinetobacter baumannii co-infection in patients with avian influenza A (H7N9) virus infection has been described as one of the most prevalent bacterial co-infections. However, the clinical and laboratory features of this entity of H7N9 and A. baumannii co-infection have not been systematically investigated.  METHODS:

We collected clinical and laboratory data from laboratory-confirmed H7N9 cases co-infected by A. baumannii. H7N9 patients without bacterial co-infection and patients with A. baumannii-related pneumonia in the same hospital during the same period were recruited as controls. The antibiotic resistance features and the corresponding genome determinants of A. baumannii and the immune responses of the patients were tested through the respiratory and peripheral blood specimens. RESULTS: Invasive mechanical ventilation was the most significant risk factor for the nosocomial A. baumannii co-infection in H7N9 patients. The co-infection resulted in severe clinical manifestation which was associated with the dysregulation of immune responses including deranged T-cell counts, antigen-specific T-cell responses and plasma cytokines. The emergence of genome variations of extensively drug-resistant A. baumannii associated with acquired polymyxin resistance contributed to the fatal outcome of a co-infected patient. CONCLUSIONS:
The co-infection of H7N9 patients by extensively drug-resistant A. baumannii with H7N9 infection is an important issue which deserves attention. The dysfunctions of immune responses were associated with the co-infection and were correlated with the disease severity. These data provide useful reference for the diagnosis and treatment of H7N9 infection.

https://www.ncbi.nlm.nih.gov/pubmed/30126042

Clin Respir J. 2018 Nov;12(11):2539-2545. doi: 10.1111/crj.12953. Epub 2018 Oct 22.

A study on mother-to-fetus/infant transmission of influenza A(H7N9) virus: Two case reports and a review of literature.

Wang J¹, Xu H², Mu C¹, Chen C¹, Guo L³, Chen L⁴, Huang JA¹, Guo Q².Abstract OBJECTIVES:

The prevention strategies for mother-to-fetus/infant transmission of H7N9 virus have not been well understood, and the study on this subject will provide further insights.  METHODS:
Reverse transcriptase polymerase chain reaction assay was undertaken to detect H7N9 virus in samples from a pregnant women, a postpartum woman, and their fetus/infant. Pathological features of tissues from the dead fetus were evaluated with hematoxylin and eosin staining. Hemagglutination inhibition assay was used to detect virus-specific antibodies. Furthermore, relevant literatures were reviewed and analyzed. RESULTS:
A 28-year-old pregnant woman was hospitalized for H7N9 infection and prescribed with oseltamivir and peramivir for 2 days before admission. The fetal heart beating stopped on day 4, the dead fetus was delivered on day 13, and the woman expired on day 26. All fetal tissues were H7N9 virus-negative. A 28-year-old woman delivered a newborn on December 20, 2016. Five days later, she developed influenza-like symptoms and was confirmed with H7N9 infection. She had close contact with her infant for 9 days. Oseltamivir and peramivir were prescribed within 2 days after illness onset. A throat swab and a pair of serum samples from the infant were all negative for H7N9 virus during 4-week follow-up. In total, ten studies referring to transplacental transmission and four reports on maternal infection of H7N9 virus were reviewed and analyzed. CONCLUSION:
No evidence showed H7N9 virus infection in both fetus and infant. The early administration of neuraminidase inhibitor seemed beneficial in preventing mother-to-fetus/infant transmission of H7N9 virus.

https://www.ncbi.nlm.nih.gov/pubmed/30069787

Curr Infect Dis Rep. 2018 Aug 1;20(10):38. doi: 10.1007/s11908-018-0643-8.

Zoonotic Influenza and Human Health-Part 2: Clinical Features, Diagnosis, Treatment, and Prevention Strategies.

Mehta K¹, Goneau LW^2,3, Wong J^1,4,5, L'Huillier AG¹, Gubbay JB^6,7,8.Abstract PURPOSE OF REVIEW:

Zoonotic influenza viruses are those influenza viruses that cross the animal-human barrier and can cause disease in humans, manifesting from minor respiratory illnesses to multiorgan dysfunction. The increasing incidence of infections caused by these viruses worldwide has necessitated focused attention to improve both diagnostic as well as treatment modalities. In this second part of a two-part review, we discuss the clinical features, diagnostic modalities, and treatment of zoonotic influenza, and provide an overview of prevention strategies. RECENT FINDINGS:
Illnesses caused by novel reassortant avian influenza viruses continue to be detected and described; most recently, 

• a human case of avian influenza A(H7N4) has been described from China. 
• We continue to witness increasing rates of A(H7N9) infections, with the latest (fifth) wave, from late 2016 to 2017, being the largest to date. 
• The case fatality rate for A(H7N9)
•  and A(H5N1) infections among humans is much higher than
•  that of seasonal influenza infections. 
• Since the emergence of the A(H1N1) 2009 pandemic, 
• and subsequently A(H7N9), testing and surveillance for novel influenzas have become more effective.

 Various newer treatment options, including peramivir, favipiravir (T-705), and DAS181, and human or murine monoclonal antibodies have been evaluated in vitro and in animal models. Armed with robust diagnostic modalities, antiviral medications, vaccines, and advanced surveillance systems, we are today better prepared to face a new influenza pandemic and to limit the burden of zoonotic influenza than ever before. Sustained efforts and robust research are necessary to efficiently deal with the highly mutagenic zoonotic influenza viruses.

https://www.ncbi.nlm.nih.gov/pubmed/29996349

Zhonghua Jie He He Hu Xi Za Zhi. 2018 Jul 12;41(7):534-538. doi: 10.3760/cma.j.issn.1001-0939.2018.07.006.

[Analysis of 15 cases of avian influenza virus (H7N9) infection].

[Article in Chinese; Abstract available in Chinese from the publisher]

Yu WQ¹, Ding MD, Dai GH, Gu CJ, Xue L, Chen Y, Zhou DM, Xian JC, Xu HT. Abstract

Objective: To describe the clinical, chest imaging, pathological manifestations and therapeutic experience of human infection with A/H7N9 virus. Methods: The features of 15 laboratory-confirmed cases of human infection with A/H7N9 virus in Taizhou, Jiangsu Province were retrospectively analyzed. Results: The 15 patients with confirmed viral pneumonia included 12 males and 3 females, with a median age of 61 years(ranging from 33 to 81 years). Twelve patients had a history of exposure to the poultry trading places, or direct contact with ill/dead avian, while 3 patients denied exposure or contact. The most common initial symptoms were fever, coughing, and respiratory distress. The illness progressed rapidly to acute respiratory distress syndrome (ARDS). Lab tests showed normal (8 cases) or decreased (7 cases)white blood cell count , decreased (13 cases) lymphocyte count and proportion , increased creatine kinase (CK, 12 cases) and lactate dehydrogenase (LDH, 15 cases), and respiratory failure (13 cases). Chest radiographic examination showed that the most common features were inflammatory infiltration in the lung, with partial consolidation. The average time of the diagnosis with influenza viral nucleic acid and onset of an oral anti-influenza drug were 7.1 days and 6.5 days. All patients were treated by antiviral drugs (oral oseltamivir 150 mg q12 h and/or intravenous paramivir 600 mg qd), with mechanical ventilation in 9 cases, glucocorticoid therapy in 5 cases (intravenous methylprednisolone in 3 and dexamethasone in 2 patients), extracorporeal membrane oxygenation (ECMO) therapy in 2 cases, continuous renal replacement therapy (CRRT) in 6 cases, and artificial liver therapy in 1 case. The pulmonary pathology was observed from post-mortem biopsy for 2 fatal cases. Patient 1 had diffuse alveolar damage with inflammatory exudation, hyaline membrane formation, and cellular infiltration. Patient 2 had widened alveolar septum, lymphocyte and monocyte cell infiltration in the alveolar septa, and interstitial fibrous proliferation. Nine patients were discharged, and 6 died. Conclusions: Patients with influenza A/H7N9 virus mostly presented with fever, cough, and were prone to progression to viral pneumonia. Once acute respiratory distress and important organ dysfunction occurred, the fatality rate was higher. Early diagnosis and rational treatment were critical for better outcomes.

https://www.ncbi.nlm.nih.gov/pubmed/29617693

Cell Physiol Biochem. 2018;46(2):633-643. doi: 10.1159/000488631. Epub 2018 Mar 28.The Protective Effects of the A/ZJU01/ PR8/2013 Split H7N9 Avian Influenza Vaccine Against Highly Pathogenic H7N9 in BALB/c Mice.

Wu XX¹, Deng XL², Yu DS¹, Yao W³, Ou HL¹, Weng TH¹, Hu CY¹, Hu FY², Wu NP¹, Yao H¹, Zhang FC², Li LJ¹. Abstract

BACKGROUND/AIMS: Since the first case of novel H7N9 infection was reported, China has experienced five epidemics of H7N9. During the fifth wave, a highly pathogenic H7N9 strain emerged. In order to assess whether the H7N9 vaccine based on A/Zhejiang/DTID-ZJU01/2013(H7N9) was effective in protecting against highly pathogenic H7N9, we conducted this study. METHODS: Groups of mice were immunized twice by intraperitoneal injection with 500 µl of either split vaccine alone or MF59-adjuvanted vaccine. Serum was collected 2 weeks after the second vaccine booster. The hemagglutinin inhibition test was conducted on vaccine seed and highly pathogenic H7N9 to evaluate the neutralization of highly pathogenic H7N9. We also immunized mice and challenged them with highly pathogenic H7N9. Mice were observed for illness, weight loss, and death at 1 week and 2 weeks post-infection. Then, the mice were sacrificed and lungs were removed. Antibody responses were assessed and pathological changes in the lung tissue were evaluated. RESULTS:The ability of serum to neutralize highly pathogenic H7N9 was reduced. In mice, highly pathogenic H7N9 was more virulent than A/Zhejiang/DTID-ZJU01/2013(H7N9). After challenge with highly pathogenic H7N9, all mice died while mice challenged with A/Zhejiang/DTID-ZJU01/2013(H7N9) all recovered. The A/ZJU01/PR8/2013 split H7N9 avian influenza vaccine was able to protect against infection with highly pathogenic H7N9 in mice, with or without MF59. Moreover, H7N9 vaccine adjuvanted with MF59 produced high antibody levels, which lead to better protection. CONCLUSIONS: The A/ZJU01/PR8/2013 split H7N9 avian influenza vaccine based on A/Zhejiang/DTID-ZJU01/2013(H7N9) is effective in protecting against highly pathogenic H7N9. H7N9 vaccine adjuvanted with MF59 offers better protection against infection with highly pathogenic H7N9. In order to make the H7N9 vaccine applicable to humans, further clinical trials are required to evaluate MF59 adjuvanted vaccine. Meanwhile, the vaccine strain should be updated based on the highly pathogenic H7N9 gene sequence.

© 2018 The Author(s). Published by S. Karger AG, Basel. KEYWORDS:

Highly pathogenic H7N9; MF59 adjuvant; Protective immune responses; Split H7N9 vaccine

H7N9 virusta koskevaa tiedettä

https://www.ncbi.nlm.nih.gov/pubmed/30888978

Curr Opin Infect Dis. 2019 Mar 18. doi: 10.1097/QCO.0000000000000538. [Epub ahead of print]

A delicate balancing act: immunity and immunopathology in human H7N9 influenza virus infections.

Karawita AC¹, Tong MZW¹, Short KR^1,2.

Abstract

PURPOSE OF REVIEW:

A delicate balance exists between a protective and detrimental immune response to an invading viral pathogen. Here, we review the latest advancements in our understanding of immunity and immunopathology during H7N9 influenza A virus (IAV) infections and its relevance to disease management and diagnosis.

RECENT FINDINGS:

Recent studies have highlighted the role of specific leukocytes in the pathogenesis of H7N9 IAV infections and potential diagnostic role that host cytokine profiles can play in forecasting disease severity. Furthermore, alterations in diet have emerged as a possible preventive measure for severe IAV infections.

SUMMARY:

The recent emergence and continued evolution of H7N9 IAVs have emphasized the threat that these avian viruses pose to human health. Understanding the role of the host immune response in both disease protection and pathogenesis is an essential first step in the creation of novel therapeutic and preventive measures for H7N9 IAV infections.

PMID:

30888978

DOI:

10.1097/QCO.0000000000000538

Kinaaseihin kohdistuvien lääkkeiden mahdollinen uusi indikaatio ja käyttö influenssavirusta vastaan?

https://www.ncbi.nlm.nih.gov/pubmed/30791550

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Viruses. 2019 Feb 20;11(2). pii: E171. doi: 10.3390/v11020171.

Influenza Virus Infections and Cellular Kinases.

Meineke R¹, Rimmelzwaan GF², Elbahesh H³.

Abstract

Influenza A viruses (IAVs) are a major cause of respiratory illness and are responsible for yearly epidemics associated with more than 500,000 annual deaths globally. Novel IAVs may cause pandemic outbreaks and zoonotic infections with, for example, highly pathogenic avian influenza virus (HPAIV) of the H5N1 and H7N9 subtypes, which pose a threat to public health. Treatment options are limited and emergence of strains resistant to antiviral drugs jeopardize this even further. Like all viruses, IAVs depend on host factors for every step of the virus replication cycle. Host kinases link multiple signaling pathways in respond to a myriad of stimuli, including viral infections. Their regulation of multiple response networks has justified actively targeting cellular kinases for anti-cancer therapies and immune modulators for decades. There is a growing volume of research highlighting the significant role of cellular kinases in regulating IAV infections. Their functional role is illustrated by the required phosphorylation of several IAV proteins necessary for replication and/or evasion/suppression of the innate immune response. Identified in the majority of host factor screens, functional studies further support the important role of kinases and their potential as host restriction factors. PKC, ERK, PI3K and FAK, to name a few, are kinases that regulate viral entry and replication. Additionally, kinases such as IKK, JNK and p38 MAPK are essential in mediating viral sensor signaling cascades that regulate expression of antiviral chemokines and cytokines. The feasibility of targeting kinases is steadily moving from bench to clinic and already-approved cancer drugs could potentially be repurposed for treatments of severe IAV infections. In this review, we will focus on the contribution of cellular kinases to IAV infections and their value as potential therapeutic targets.

KEYWORDS:

antivirals; influenza virus; kinases; metabolism; pathogenesis; phosphorylation; replication; small molecule inhibitors

PMID:

30791550

DOI:

10.3390/v11020171

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Table 1. Overview of cellular kinases and their role in different stages of IAV replication.

	Name	IAV Effect	In Vitro, In Vivo or Ex Vivo	Inh. vs. KO	Reference
Tyrosine	FAK	-Virus entry -Polymerase activity	In vitro	Inhibition	Elbahesh et al., 2014, 2016 [39,40]
	TrkA	-vRNA synthesis -RNP export -Budding	In vitro	Inhibition	Kumar et al., 2011a, 2011b [28,29]
	Btk	-Neutrophil regulation	In vivo	Inhibition	Florence et al., 2018 [49]
	c-Abl	-Pathogenicity mediator	In vivo	Inhibition	Hrincius et al., 2014, 2015 [50,51]
	Tyk2	-Cytokine regulation	Ex vivo	Inhibition	Berg et al., 2017 [52]
Serine/Threonine	JNK1 / JNK2	-vRNA synthesis -Autophagy -Cytokine regulation	In vivo	Inhibition	Zhang et al., 2016, 2018; Xie et al., 2014 [45,46,53]
	P38 MAPK	-vRNA synthesis -RNP export -Prevents apoptosis -Cytokine regulation -Virus entry	In vivo	Inhibition	Borgeling et al., 2014; Choi et al., 2016; Marchant et al., 2010; Amatore et al., 2014 [37,54,55,56]
	MEK	-RNP export	In vivo	Inhibition	Haasbach et al., 2017, 2013; Droebner et al., 2011 [57,58,59]
	ERK	-RNP import -RNP export	In vivo	Inhibition	Pleschka et al., 2001, Marjuki et al., 2006 [31,60]
	RSK2	-Polymerase activity	In vitro	Knockdown	Kakugawa et al., 2009 [61]
	IKK	-Cytokine regulation -Caspase regulation -RNP export -Antiviral response modification	In vitro	Inhibition	Erhardt et al., 2013; Haasbach et al., 2013; Gao et al., 2012; Nimmerjahn et al., 2004; Wurzer et al., 2004 [62,63,64,65,66]
	IRAK-M	-Neutrophil interaction -Cytokine reg.	In vivo	KO	Seki et al., 2010 [67]
	PKC	-Endosomal entry -RNP assembly -Polymerase activity -Prevents apoptosis	In vivo	Inhibition	Mondal et al., 2017; Mitzner et al., 2009; Mahmoudian et al., 2009; Sieczkarski et al., 2003; Kurokawa et al., 1990 [30,44,68,69,70]
	GRK2	-viral uncoating	In vivo	Inhibition	Yanguez et al., 2018 [71]
	AMPK	-antiviral response	In vivo	Activation	Moseley et al., 2010 [72]
	PLK1/3/4	-unknown	ex vivo	KO	Pohl et al., 2017 [73]
Lipid	PI3K	-Virus entry -Prevents apoptosis -vRNA synthesis -RNP export -antiviral response modification	In vitro	Inhibition	Erhardt et al., 2006,2007; Shin et al., 2007; Erhardt and Ludwig, 2009; Ehrhardt, 2011; Marjuki et al., 2011 [38,41,74,75,76,77]
	SphK1 / SphK2	-vRNA synthesis -RNP export	In vivo	Inhibition	Xia et al., 2018; Seo et al., 2013 [78,79]

Open Access

Viruses 2019, 11(2), 171; doi:10.3390/v11020171

1. Introduction

Influenza A (IAV) and B (IBV) viruses are important causes of upper respiratory tract infections [1]. IAV can cause severe acute respiratory disease with an attack rate of 5–10% in adults and 20–30% in children annually [2,3]. The significant public health burden caused by IAV infections is exemplified by the annual fatal cases globally, which number 290,000–650,000 [4]. Most at risk are children and the elderly, accounting for ~90% of case fatalities and/or complications [5,6]. Occasionally, novel antigenically distinct influenza A viruses emerge that may cause pandemic outbreaks as has occurred in 1918, 1957, 1968 and 2009. Unlike IAV, IBV viruses do not continuously circulate in animals and are therefore less likely to be associated with zoonotic transmission or pandemics [7]. However, they do co-circulate with IAV and can be significant contributors of influenza-related morbidity and mortality [7,8,9]. Vaccination is the preferred intervention against influenza viruses and helps to limit the impact influenza outbreaks may have. In addition, antiviral drugs are available for the treatment of influenza virus infections. The surface glycoprotein hemagglutinin (HA) is the major target for the induction of virus-neutralizing antibodies by vaccination. Currently available antiviral drugs against influenza inhibit the enzymatic activity of the viral neuraminidase (neuraminidase inhibitors (NAIs)), inhibit the viral M2 ion channels or inhibit viral RNA transcription by targeting components of the polymerase complex; all of which ultimately result in inhibition of virus replication [10,11]. The use of antiviral drugs may lead to the emergence of strains that have become resistant to these drugs by the accumulation of mutations greatly reducing their efficacy [12]. This, of course, is an important drawback and there is a need for treatment options that do not suffer from the emergence of resistant strains***. Drugs that target host factors critical for virus replication may therefore be an attractive alternative.

IAVs are members of the Orthomyxoviridae family and have a negative-sense single-stranded RNA genome. Attachment of IAV to cell-surface receptors, containing either α2,3- or α2,6-linked sialic acid residues, initiates signaling cascades that facilitate internalization of the virus via receptor mediated endocytosis. During endosomal trafficking, pH-dependent fusion of viral and endosomal membranes leads to release of viral ribonucleoproteins (vRNPs) into the cellular cytoplasm where released vRNPs are shuttled to the nucleus for replication and transcription of viral RNA; all of which require host cell machinery [13]. These early events ultimately trigger multiple anti- and pro-viral pathways utilized, suppressed or evaded by IAV. The robust production of pro-inflammatory cytokines and chemokines observed during severe IAV infections is often referred to as a “cytokine-storm” (reviewed in [14]). This dysregulated immune response is associated with severe influenza induced pneumonia that can be fatal, especially in susceptible populations including children, older adults and the immunocompromised [15].

In contrast to IAV, IBV is understudied, with only a few studies addressing the role of host factors, and specifically kinases, and their role during IBV infections. A better understanding of the viral and cellular processes, mechanisms and interactions is required to develop new treatment options [7]. Considering the overlap of IAV- and IBV-utilized kinases and their related cellular signaling cascades to prime viral replication, defining these pathways is likely to help in developing comprehensive ***host-targeted antivirals against IAV and IBV.

Kinases link a myriad of external stimuli with downstream effectors through phosphorylation of proteins and/or lipids. So far, more than 500 kinases have been identified in the human kinome [16]. These kinases are typically categorized based on their phosphorylation substrate: tyrosine, serine/threonine or lipids; as well as kinases that have dual-specificity. Target residues (Tyr, Ser, Thr) are generally within well-defined consensus sequence motifs recognized by a given kinase [17,18,19]. Interestingly, the distribution of protein phosphorylation in eukaryotic cells is distributed at a ratio of ~1000:100:1 (serine:threonine:tyrosine) [20]. Phosphorylation can alter activity and subcellular localization, as well as biomolecular interactions [21]. In addition, phosphorylation can promote scaffolding activities of proteins that enhance, inhibit and modulate the substrates interaction with other cellular components [22]. Aberrant kinase activity is typically associated with several pathologies including cancer, diabetes or neurodegenerative diseases, which has led to the development and investigation of several kinase inhibitors for clinical use [23,24,25,26]. However, as of 2018,*** only 30 small-molecule kinase inhibitors (SMKIs) have gained FDA-approval for clinical use [26,27]. No SMKIs are currently under clinical trial investigation against influenza virus infections.*** IAV does not encode a kinase and is therefore dependent on cellular kinases to directly or indirectly, regulate phosphorylation-dependent processes including viral entry and uncoating, viral RNA and protein synthesis, protein relocation and release of viral particles [28,29,30,31]. In addition, several studies have illustrated the importance of IAV-protein phosphorylation in regulating viral replication and evasion/suppression of innate immune signaling cascades that control expression of pro inflammatory chemokines and cytokines response [32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]. Moreover, RNAi screenings continue to add to the list of host factors that impact IAV replication [48].

Therefore, a better understanding is required of how influenza viruses utilize these critical host factors and how these factors regulate species-specific host adaption and pathogenesis of influenza viruses. This review aims to discuss current knowledge of the role cellular kinases play during in vitro and in vivo influenza virus infections ***as potential antiviral targets (Table 1) (Figure 1). Given the current state of knowledge, this review will be largely focused on IAV studies; however, IBV studies will be highlighted when possible.

Figure 1. Host kinases and known roles during IAV infections. Schematic organizing host kinases based on kinase family, signaling pathway involved, specific kinase and effect of inhibition (from innermost to outermost ring; white cone).

Table 1. Overview of cellular kinases and their role in different stages of IAV replication.

2. Phosphorylation of Influenza Virus Proteins

Phosphorylation of IAV and IBV has been reported with some conservation across influenza virus species [34]. IAV protein-phosphorylation regulates different stages of the viral cycle by either promoting replication or evading/suppressing the innate immune response [32,33,34,35,36,69]. Moreover, ***0treatment with kinase inhibitors affects influenza A virus RNA and protein synthesis, shuttling of viral proteins between the cytoplasm and nucleus, and virion release [28,29,30,31,80]. The nonstructural protein NS1 is a multifunctional immune modulator that counteracts host defenses [81,82]. NS1 phosphorylation at T215, S42 and S48 is thought to regulate the dsRNA binding capacity of NS1, which promotes evasion of the innate immune response [33,83]. Akt, an effector kinase of both the PI3K and ERK pathways, is responsible for T215 phosphorylation, which consequently results in viral entry and genome replication suppression following Akt inhibitor treatment [84,85]. Additionally, mutation of S42 eliminates the interaction of NS1 with dsRNA and attenuates viral replication [33,84]. T132 phosphorylation of the M1 protein controls its nuclear import, which is critical for viral replication. The Janus kinase 2 (JAK2) inhibitor AG490 prevents nuclear import of M1, suggesting that JAK2 might be responsible for M1 T132 phosphorylation [34,35]. Inhibition of IAV nucleoprotein (NP) phosphorylation leads to its nuclear retention that is largely regulated by several phosphorylation sites, including S9, Y10, S165 and Y296. Mutation of these sites results in decreased viral replication in vitro and in vivo largely through disruption of interactions with cellular importin-α and chromosomal maintenance 1 proteins [34,36,86].

3. Tyrosine Kinases (TK)

Tyrosine kinases (TK) are a subgroub of ~90 kinases within the human kinome that phosphorylate tyrosine amino acid residues; this can lead to conformational changes in a given protein or even serve as a scaffolding site to facilitate protein–protein interactions. TKs are further classified into receptor tyrosine kinases (RTK) and non-receptor tyrosine kinases (non-RTK). Non-RTK act as intracellular signal transducers, mediating the signaling of cell-surface receptors for cytokines, growth factors and other ligands [16]. Several phosphorylation sites (S, T and Y) in IAV and IBV proteins have been identified [34]. Based on additional sequence analysis of  about 50,000 strains (www.fludb.org), we identified highly conserved tyrosine residues in replication complex proteins (PA, PB1, PB2) and NP proteins of all IAV subtypes. This level of conservation suggests an evolutionary importance that might be exploited in understanding conserved functions and developing broadly active therapeutics targeting TK. Interestingly, while many of these phosphorylation sites have been previously reported and their importance demonstrated or inferred, the kinases that carry out their phosphorylation have yet to be experimentally validated.

Nerve growth factor receptor (TrkA) is a receptor tyrosine kinase that was shown to play a role in IAV viral RNA synthesis, vRNP nuclear export and virion release. In vitro inhibition of TrkA has been shown to diminish IAV RNA (vRNA, mRNA and cRNA) synthesis independently of NFκB signaling [29]. Interestingly, this reduction in RNA synthesis was largely due to direct inhibition of CRM1-mediated export and subsequent nuclear retention of IAV RNPs [29]. In addition, TrkA inhibition leads to reduced activation of the lipid biosynthesis enzyme, farnesyl diphosphate synthase (FPPS), which is known to modulate virion budding [28]. However, the exact mechanism of TrkA-mediated FPPS regulation remains undefined.

Focal adhesion kinase (FAK) is a non-RTK and a component of focal adhesions that tether the actin cytoskeleton to the extracellular matrix. We previously showed that FAK links phosphatidylinositol-3 kinase (PI3K) activation and cytoskeletal reorganization required for endosomal trafficking during IAV entry [40]. Furthermore, FAK positively regulates IAV replication and polymerase activity of different IAV strains/subtypes [39,40]. Others have also reported roles for FAK during other viral infections [87,88,89,90,91,92]. FAK can modulate the cellular immune response by regulating various functions of T cells, B cells and macrophages [93,94,95]. Consistent with this, we have observed FAK dependent regulation of innate immune responses during severe IAV infection in mice [96].

Abl1 (also known as Abelson murine leukemia viral oncogene homolog 1 or c-Abl) is a cytoplasmic and nuclear non-RTK that phosphorylates CRK (also known as p38 or proto-oncogene c-CRK), an adaptor protein required for efficient replication of avian influenza viruses and subsequent JNK-mediated apoptosis [97]. The viral nonstructural protein 1 (NS1) can disrupt Abl1-CRK interactions via its Src homology binding motifs and thereby inhibit CRK phosphorylation, ultimately resulting in IAV-subtype specific pathogenicity as shown for the 1918 pandemic H1N1 virus [50,51].

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) due to immune cell infiltration during severe IAV and ensuing secondary bacterial infections can result in respiratory failure and are the main causes of death in influenza-infected patients [98]. Bruton’s tyrosine kinase (Btk) can regulate TLR4-mediated activation in human neutrophils [99]. Interestingly, chemical inhibition of Btk can alleviate IAV induced ARDS symptoms in mice [49]. This effect is likely due to limiting damaging neutrophil activity and production of pro-inflammatory chemokines and cytokines including TNF-α, IL-1β, IL-6, KC, and MCP-1 during acute lung injury [49].

The IFN receptor I and III-associated tyrosine kinase 2 (Tyk2) has emerged as an important host factor targeting secondary bacterial infections. The virally induced retention of IL-1β and GM-CSF diminishes the bacterial-induced innate immune response that may allow the establishment of secondary bacterial infection. Specific ex vivo inhibition of Tyk2 resulted in impaired bacterial growth due to restored IL-1β and GM-CSF levels in human alveolar tissues [52].

4. Serine/Threonine Kinases (STK)

Serine/Threonine kinases (STKs) facilitate phosphorylation of protein at either serine or threonine residues. STKs are central components of many cellular signaling pathways including Raf/MEK/ERK, nuclear factor kappa-B (NF-κB) and PKC [100,101,102]. The Ras-dependent Raf/MEK/ERK pathway is activated by almost all cytokines and growth factors that bind to receptor tyrosine kinases, cytokine receptors and G-protein coupled receptors [43]. Accordingly, the importance of Raf/MEK/ERK signaling for effective IAV replication has previously been demonstrated [31,60].

IAVs utilize multiple mechanisms to hijack STKs to evade subsequent innate immune responses.

 c-Jun N-terminal kinases 1 and 2 (JNK1/JNK2) can regulate pro-inflammatory response induction and are upregulated by several IAV strains. IAV-mediated induction of JNK1/JNK2 activity triggers the Raf/MEK/ERK pathway, mediating production of chemokines and cytokines including tumor necrosis factor alpha (TNF-α), interferon β (IFN-β) and interleukin 6 (IL-6) [45]. Interestingly, recent studies suggest that JNK1-dependent phosphorylation of Bcl-2, a process normally observed as a starvation induced autophagy signal, is promoted by viral JNK1 activation resulting in virus-induced autophagy [46]. Chemical inhibition of JNK1/JNK2 resulted in reduced levels of pro-inflammatory cytokines in vivo [45]. Additionally, in vitro inhibition of JNK1/JNK2 results in impaired vRNA synthesis; however, the mechanism is yet to be defined [53].

As a member of the mitogen-activated protein kinase (MAPK) family, p38 is involved in several steps of the IAV infection cycle. IAV infected cells expressing the antiapoptotic protein Bcl-2 show reduced viral titers due to reduced vRNP export from the nucleus with no effect on virally induced apoptosis. The antiapoptotic effect of Bcl-2 was reduced by phosphorylation of its threonine 56 and serine 87 residues by virus-induced p38 activity. Inhibition of p38 diminished viral replication, vRNP export and apoptosis [103]. During early stages, TLR4 mediated viral activation of p38 MAPK is important for viral entry and replication [37,55]. Furthermore, in vivo inhibition of p38 MAPK directly limited excessive cytokine expression through an IFN-dependent mechanism. This regulation is mediated via phosphorylation of STAT1 and subsequent engagement of the IFNβ promotor to regulate IFN-stimulated gene (ISG) expression [54]. Influenza virus induced perturbations of the intracellular redox balance resulting in increased production of reactive oxygen species (ROS) can also activate p38 [56,104]. Furthermore, NADPH oxidase 4 (NOX4)-regulated p38 and ERK activation leads to increased ROS production during IAV infections in vitro [56,105,106]. Interestingly, mouse experiments suggest that the effects of Bcl-2 and NOX4 may be gender dependent. Female mice exhibited reduced clinical symptoms and viral titers; in contrast, higher IAV replication in male mice correlated with higher expression of NOX4 and phosphorylation of p38 [107].

The NF-κB signaling pathway is a central regulator of innate immune responses and the IkB kinase (IKK) is a direct target of the viral NS1 protein in counteracting the NF-κB mediated cellular antiviral response [63,108]. However, the majority of publications have shown that inhibition of NF-κB signaling diminishes viral replication in vitro and in vivo [64,65,66]; more specifically, lowered levels of pro-inflammatory factors, reduced caspase activity and therefore impaired caspase-mediated nuclear export of vRNP [62].

 Interleukin 1 receptor-associated kinase-M (IRAK-M) is a NF-κB signaling related cellular kinase. During IAV induced pneumonia, IRAK-M acts a central regulator of inflammation of mucosal tissue in the respiratory tract. IRAK-M knockout mice challenged with IAV showed strongly increased lethality rate and decreased viral clearance [67].

The successful nuclear export of vRNP has been shown to depend directly on the viral activation of the Raf/MEK/ERK signaling pathway [31,109].

 MAPK kinase (MEK) and extracellular signal-regulated kinase (ERK), belong to the group of classical mitogen-activated protein kinases (MAPK). MEKs have been shown to regulate IAV and IBV replication [31,109]. Several MEK inhibitors resulted in vRNP retention, reduced titers of progeny virus in vitro, and also improved mouse survival in vivo [57,58,59].
During early stages of IAV infection, ERK regulates the vacuolar H⁺-ATPase (V-ATPase) activity to mediate pH-dependent acidification of endosomes and subsequent fusion of the viral and endosomal membranes [41]. In vitro inhibition of ERK, a direct downstream mediator of MEK, impedes IAV vRNP nuclear import as well as export [41,60].

 IAVs activation of Raf/MEK/ERK signaling also induces p90 ribosomal s6 kinases (RSK), which play an important role as downstream mediators of ERK signaling [61,110]. RSK2 is involved in regulation of cell growth and proliferation. RSK2 knockdown using shRNAs results in increased IAV and IBV replication and IAV polymerase activity [61]. Inhibition of RSK2 blocked IAV-induced phosphorylation of double-stranded RNA-activated protein kinase (PKR), one of 4 known kinases (PKR, HRI, PERK and GCN2) that phosphorylate the translation-initiation factor elF2 during stress responses resulting in inhibition of cap-dependent translation of cellular and viral proteins [61,111].
 PKR activation by influenza virus infections is well established and the virus has evolved multiple mechanisms to suppress PKR activation. Furthermore, IAV-dependent stimulation of NF-κB and IFN-β was impaired by RSK2 inhibition, suggesting an effect on the cellular antiviral response [61].

In addition to Raf/MEK/ERK kinases, the G protein-coupled receptor kinases (GRKs) are also implicated in the induction of innate immunity pathways. Recent phosphoproteomic studies identified GRK2 as an important junction of cellular signaling pathways activated by IAV. In vitro and in vivo inhibition of GRK2 resulted in decreased viral replication [71], while the exact function of GRK2 remains unclear.

 Polo-like kinases (PLK) act as GRK nodes of cellular signaling and are crucial regulators of cell division and the cell cycle [112]. PLK1 has been described as acting as a pro-viral host factor for several viruses by phospho-regulating viral proteins [113,114]. A recent study shows that in vitro and ex vivo inhibition, as well as knockdown of PLK1, PLK3 and PLK4, results in impaired IAV replication [73].

Protein kinase C (PKC) is a STK that regulates multiple cellular processes including proliferation, differentiation, apoptosis and angiogenesis. The functional versatility of PKC is dependent on its various isoforms responding to different stimuli. The complexity of eleven different PKC isoforms expressed in most tissues also limits understanding of their function within different cell types [115]. Nevertheless, Kurokawa et al. showed almost 30 years ago that general in vitro inhibition of PKC results in reduced viral protein synthesis [30]. More recent studies have further defined the function of PKC isoforms and their involvement in IAV infections. Treatment of cells with bisindolylmaleimide, a highly specific PKC inhibitor that has activity against most PKC isoforms, reversibly inhibits virus entry by blocking endosomal trafficking and virion uncoating of both IAV and IBV [80]. Phosphorylation of the viral proteins PB1 and NS1, important for polymerase activity and efficient viral replication, has been shown to be PKCα dependent in vitro [68] and for PB1 in vivo [69]. In PKCβII kinase-dead cells, IAV is retained in late endosomal compartments, suggesting PKCβII as an important modulator of IAV entry [44]. PKCδ, interaction with the IAV polymerase subunit PB2, regulates NP oligomerization and vRNP assembly, and ablation of PKCδ impaired replication of the viral genome in vitro [70].

5. Lipid Kinases (LK)

Lipid kinases are key mediators of intracellular signaling, central carbon and lipid metabolism, apoptosis and cell proliferation through phosphorylation of lipid residues. Several lipid kinases have been implicated in several steps of IAV replication and in modulating cellular antiviral responses [38,79,116,117,118].

One of the central lipid kinases is PI3K, which phosphorylates inositol phospholipids [119]. PI3K and its downstream effectors, Akt and mammalian target of rapamycin (mTOR), form a key signaling nexus that regulates cell differentiation, translation and metabolism [120].

Furthermore, it is involved in cross-interaction with other cellular signaling pathways including Raf/MEK/ERK and NF-κB pathways [121].
 Early and late PI3K during IAV infections are key events required for IAV replication with distinct outcomes at different times of infection [38].
Early PI3K activity is triggered by viral attachment and mediates IAV entry [75].
Later during the infection, IAV NS1 suppresses PI3K activity via direct interactions with the p85 regulatory subunit. These interactions ultimately prevent AKT-mediated apoptosis, IRF-3 innate immune responses, vRNA synthesis and nuclear vRNP export

[38,74,75,76,77,122,123]. It should be noted that IBV only minimally induces later PI3K activation or apoptosis. Furthermore, in contrast to IAV NS1, IBV NS1 is dispensable for the antiapoptotic effects of PI3K activation suggesting IBV has developed NS1-independent mechanisms to suppress apoptosis [116,124].

Sphingosin kinases (SphK1 and SphK2) are lipid kinases that control conversion of sphingosine to bioactive lipid sphingosine 1-phosphate (S1P) [125], a known modulator of Raf/MEK/ERK, NF-κB and PI3K/AKT/mTOR signaling pathways and regulator of apoptosis [126]. IAV upregulates SphK in in vitro infected cells influencing cellular signaling and promoting efficient influenza virus replication [78,79].
 Chemical inhibition of SphK1 results in reduced vRNA synthesis via suppression of NF-κB activity and reduced vRNP nuclear export due to impaired activation of ERK and AKT [78]. SphK2 knockdown has also been shown to reduce IAV replication in vitro. Moreover, in vivo inhibition of SphK1 and SphK2 resulted in prolonged survival of mice challenged with IAV [79].

6. Linking Metabolism and Innate Immunity

Like many pathologic conditions, IAV infection alters the metabolic landscape and most of these alterations are mediated by kinases resulting in direct or indirect effect on IAV replication, infection kinetics and pathogenicity. Consistently, the majority of host-cell alterations following IAV infections are in metabolic pathways [127]. Virus regulated kinase activity can have a major influence on cellular metabolism.

AMP-activated protein kinase (AMPK) is a major sensor and regulatory master switch of carbohydrate metabolism, and is directly involved in insulin signaling and lipid metabolism. It links central carbon metabolism and glucose availability with the host innate immune response [128,129,130,131].
AMPK activity is modulated by intracellular calcium levels and this activity can regulate the stimulator of interferon genes (STING) through UNC-51-like kinase 1 (ULK1) activation. STING serves as a crucial factor of the innate immune response and an essential mediator for recognition of intracellular bacterial and viral pathogens. STING-dependent IFNβ induction is regulated by the calcium-dependent membrane potential of mitochondrial membranes.
 In vitro inhibition of AMPK resulted in reduced TNF-α and IFN-β secretion after activation with the STING ligand 5,6-dimethyl xanthone-4 acetic acid (DMXAA) [132,133,134].
AMPK phosphorylation of multiple sites of ULK1 leads to its dissociation from AMPK and subsequent activation. ULK1 activity promotes phosphatidylinositol-3-phosphate (PI3P) synthesis that contributes to autophagosome formation in addition to JNK1 induced Bcl-2 dependent autophagy during IAV infection [46,135,136,137].

Although ER stress triggers translational shut-down through the PKR-like ER kinase (PERK), virally induced metabolic and ER stress in the context of an obese mouse model activates PKR [138]. This activation reduces cellular and viral translation and activates JNK1 and other inflammatory kinases in response [138]. Together, PKR and nutrient deprivation-dependent JNK1 activities lead to the subsequent activation of apoptosis signal regulating kinase 1 (ASK1) [139].

 Integration of AMPK and JNK with other Raf/MEK/ERK related kinases allows engagement of metabolic processes via immune response components including NF-κB, PI3K/AKT/mTOR and PKC pathways [117,118,140,141,142].
 Accordingly, the NF-κB regulating kinase, IKK, has recently been linked to glycolysis [143,144].
 In addition, IKK- and PKC-dependent serine phosphorylation of the insulin receptor, inhibits insulin signaling and directly regulates cellular lipid metabolism [145,146].

Furthermore, PKC has been described to be involved in fatty acid fate regulation, auto-stimulating kinase activity [147]. PI3K/AKT/mTOR signaling mediates its effects upstream and downstream of NF-κB, Raf/MEK/ERK and PKC pathways to regulate lipogenesis and lipid metabolism [121,131,148,149].

Recent studies suggest that inhibition of Btk leads to metabolic stress through suppression of PI3K/AKT/mTOR signaling [150], highlighting the link between metabolism and innate immunity.
Interestingly, using a PI3K/mTOR inhibitor to disrupt glucose metabolism in vitro results in reduced virus production independently of genome replication and most likely drives lipid membrane depletion due to viral budding [127].

 It is important to note that influenza virus-induced kinase activity does not only serve to evade the immune response but can also promote a pro-viral metabolic environment and responses.

7. Perspectives and Future Directions

The continued threat of severe and potentially lethal influenza A virus outbreaks is highlighted by rapid viral evolution, emergence of novel subtypes and antiviral-resistant strains and limited vaccine efficacy. Developing virus-directed antivirals is akin to hitting a moving target. Therefore, approaches that largely mitigate the potential for drug-resistance while being effective against multiple IAV subtypes and strains is highly desirable. Therapies that target host cell factors meet these criteria and are more likely to avoid exuberant immune responses that are likely to reduce disease severity and improve patient outcome.

***Kinases are ideal candidates for host-directed antiviral therapies by linking critical cellular processes utilized by most viruses. Moreover, their importance in pathologic conditions such as cancer has led to the development of ***small-molecule inhibitors and repurposing these clinically approved drugs to treat severe infectious diseases like influenza, should be exploited.

Several reports have recently highlighted critical roles for the focal adhesion kinase (FAK) pathway during infection by several viruses [87,88,89,90,91]. FAK is not only critical for embryonic development and expression of several cellular proteins, it also links integrins with actin reorganization and receptor endocytosis [151,152,153,154]. Given its role in several cancers and the unique structure of its kinase domain, FAK is an attractive target of anti-cancer therapies and several FAK inhibitors are under investigation for clinical use [155].

The FAK pathway has recently emerged as a nexus point engaging antiviral innate immune and inflammatory pathways. Accordingly, FAK is also a component of the intracellular RIG-I-like receptor antiviral pathway where it provides a link between perturbations of the cell surface receptor during viral entry and cytosolic innate immune sensors [156]. FAK modulates the cellular immune response by regulating T cells, B cells and macrophage functions [93,94,95]. FAK was also recently reported to directly phosphorylate IKKα thereby regulating canonical and non-canonical NF-κB pathways [157].

Although SMKIs have been met with often-warranted criticism, this has stemmed from a misconception in clinical literature and inaccurate distinction between in vitro/in vivo substrate (target) specificity and cell-population specificity in vivo of these SMKIs [158,159,160,161].

 Because tyrosine kinases share conserved sequences in their ATP binding sites, ATP analogs have an increased likelihood of “off-target” effects on other kinases [162]. Therefore, new small molecule inhibitors designed to avoid this problem directly interfere with FAK autophosphorylation by binding to Y397 instead of blocking ATP binding. One such compound is FAK Inhibitor I (also known as Compound 14 or Y15) which has been validated as a selective FAK inhibitor [163,164,165]. We found that Y15-treatment of various cells, or expression of kinase-dead FAK mutant (FAK-KD), provided the first evidence that FAK is activated by IAV attachment and that FAK kinase activity is critical for efficient endosomal virus trafficking [40].
 We also reported that inhibitor-treatment or FAK-KD expression reduced polymerase activity of multiple IAV subtypes including highly pathogenic H5N1 and H7N9. Importantly, we observed FAK interactions with the viral NP [39]; however, the significance of this interaction is still under investigation.

 Defactinib is an FDA approved FAK inhibitor that has dual activity against FAK and the related kinase Pyk2 and is therefore expected to have different effects than Y15 due to differences in specificities. Our published data utilizing Y15 clearly indicates a FAK specific role in IAV replication. However, given that Pyk2 has overlapping roles in immune cell development and functions [93,94,95], it is possible that inhibiting both kinases will have alternative outcomes. While this might first be viewed as a cause for concern, it provides the opportunity to potentially fine tune treatments where either FAK or Pyk2 or both can be inhibited depending on the timing of treatment (early vs late in infection).

Investigating ***repurposed cancer drugs for their antiviral properties and their potential immunomodulatory effects during infection will improve our understanding of the role of the respective kinases in the pathogenesis of IAV infections and may lead to the development of novel intervention strategies.
Further research on the role of host kinases in virus-induced metabolic changes is warranted and will likely open-up additional avenues of basic and translational research.

Author Contributions

R.M., G.F.R. and H.E. conceptualized and composed the manuscript. G.F.R. and H.E. oversaw all aspects of the manuscript preparation.

Funding

This research and the APC was funded by the Alexander von Humboldt Foundation in the framework of the Alexander von Humboldt Professorship endowed by the German Federal Ministry of Education and Research.

Conflicts of Interest

The authors declare no conflict of interest.

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