TMPRSS2 Is a Host Factor That Is Essential for Pneumotropism and Pathogenicity of H7N9 Influenza A Virus in Mice

Tarnow, Carolin; Engels, Geraldine; Arendt, A; Schwalm, Folker; Sediri, Hanna; Preuß, Annette; Nelson, Peter S.; Garten, Wolfgang; Klenk, Hans Dieter; Gabriel, Gülşah; Böttcher‐Friebertshäuser, Eva

doi:10.1128/jvi.03799-13

Cited by 131 publications

(160 citation statements)

References 49 publications

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“…TMPRSS2 appears to be essential for influenza H1N1 virus to be pathogenic in mice but not for H3N2 virus pathogenicity (9). H1N1 virus replication was suppressed in the respiratory tract of TMPRSS2 Ϫ/Ϫ mice, while H3N2 virus replication was only marginally affected (11). It was recently proposed that TMPRSS4 plus TMPRSS2 activate H3N2 viruses in mice (12).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

Magnen

Gueugnon

Guillon

et al. 2017

J Virol

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Hemagglutinin (HA) of influenza virus must be activated by proteolysis before the virus can become infectious. Previous studies indicated that HA cleavage is driven by membrane-bound or extracellular serine proteases in the respiratory tract. However, there is still uncertainty as to which proteases are critical for activating HAs of seasonal influenza A viruses (IAVs) in humans. This study focuses on human KLK1 and KLK5, 2 of the 15 serine proteases known as the kallikrein-related peptidases (KLKs). We find that their mRNA expression in primary human bronchial cells is stimulated by IAV infection. Both enzymes cleaved recombinant HA from several strains of the H1 and/or H3 virus subtype in vitro, but only KLK5 promoted the infectivity of A/Puerto Rico/8/34 (H1N1) and A/Scotland/20/74 (H3N2) virions in MDCK cells. We assessed the ability of treated viruses to initiate influenza in mice. The nasal instillation of only the KLK5-treated virus resulted in weight loss and lethal outcomes. The secretion of this protease in the human lower respiratory tract is enhanced during influenza. Moreover, we show that pretreatment of airway secretions with a KLK5-selective inhibitor significantly reduced the activation of influenza A/Scotland/20/74 virions, providing further evidence of its importance. Differently, increased KLK1 secretion appeared to be associated with the recruitment of inflammatory cells in human airways regardless of the origin of inflammation. Thus, our findings point to the involvement of KLK5 in the proteolytic activation and spread of seasonal influenza viruses in humans.IMPORTANCE Influenza A viruses (IAVs) cause acute infection of the respiratory tract that affects millions of people during seasonal outbreaks every year. Cleavage of the hemagglutinin precursor by host proteases is a critical step in the life cycle of these viruses. Consequently, host proteases that activate HA can be considered promising targets for the development of new antivirals. However, the specific proteases that activate seasonal influenza viruses, especially H3N2 viruses, in the human respiratory tract have remain undefined despite many years of work. Here we demonstrate that the secreted, extracellular protease KLK5 (kallikrein-related peptidase 5) is efficient in promoting the infectivity of H3N2 IAV in vitro and in vivo. Furthermore, we found that its secretion was selectively enhanced in the human lower respiratory tract during a seasonal outbreak dominated by an H3N2 virus. Collectively, our data support the clinical relevance of this protease in human influenza pathogenesis.

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Section: Discussionmentioning

confidence: 99%

“…Although TMPRSS2 is a marker of susceptibility to severe A (H1N1)pdm09 influenza virus (8), there is no clinical data indicating the involvement of a specific protease in the activation of seasonal IAV. However, in mice, TMPRSS2 has been identified as being essential for the spread of H1N1 IAV (9)(10)(11) and of H3N2 IAV in association with TMPRSS4 (12).…”

mentioning

confidence: 99%

Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

Magnen

Gueugnon

Guillon

et al. 2017

J Virol

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“…It was previously shown that TMPRSS2 allows HA cleavage thus promoting viral spread. Knockout of TMPRSS2 could prevent the propagation of H1N1, H7N9 viruses into the lungs of mice, however, TMPRSS2 seemed to play only marginal role in H3N2-caused infection 23,24 .…”

Section: Discussionmentioning

confidence: 99%

In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

Pászti-Gere

Czimmermann

Ujhelyi

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The transmembrane serine protease, TMPRSS2 is an important target in the treatment of seasonal influenza infections and contributes to prostate carcinogenesis and metastasis. In this study, the effect of the synthetic TMPRSS2 inhibitor I-432 on jejunal IPEC-J2 cell monolayers cultured on membrane inserts was characterized. Using a fluorogenic substrate, it was found that the apical addition of I-432 could suppress trypsin-like activity in the supernatants of IPEC-J2 cells. The inhibition of TMPRSS2 did not affect physiologically produced hydrogen peroxide levels in the apical and in basolateral compartments. Loss of expression of the TMPRSS2 serine protease domain (28 kDa) was also observed when cells were pre-exposed to I-432. Partial decrease in immunofluorescent signal intensities derived from the altered distribution pattern of TMPRSS2 was detected after a 48 h long incubation of IPEC-J2 cells with the inhibitor indicating the efficacy of TMPRSS2 inhibition via I-432 administration in vitro.

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“…Our group (1) and Hatesuer et al (2) showed that TMPRSS2 is essential for proteolytic activation of both H1N1 and H3N2 subtype IAVs. However, Tarnow et al (3) reported that TMPRSS2 is not critical for activation of H3N2 IAV. Since the three groups used different H3N2 IAV strains, the discrepancy likely arose from possible variations in HA among the H3N2 IAV strains.…”

mentioning

confidence: 99%

“…Using mouse models, three research groups recently demonstrated that a type II transmembrane serine protease, TMPRSS2, expressed in the airway epithelium, is critically important for HA cleavage in vivo (1)(2)(3). Mice lacking TMPRSS2 expression (TMPRSS2 knockout [tmprss2 KO ] mice) are highly tolerant of challenge infection by low-pathogenic (LP) IAVs possessing a monobasic cleavage site in HA.…”

mentioning

confidence: 99%

A Mutant H3N2 Influenza Virus Uses an Alternative Activation Mechanism in TMPRSS2 Knockout Mice by Loss of an Oligosaccharide in the Hemagglutinin Stalk Region

Sakai

Sekizuka

Ami

et al. 2015

J Virol

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e The host protease TMPRSS2 plays an essential role in proteolytic activation of the influenza A virus (IAV) hemagglutinin (HA) protein possessing a monobasic cleavage site. However, after passages in TMPRSS2 knockout mice, an H3N2 subtype IAV began to undergo cleavage activation of HA, showing high virulence in the mice due to the loss of an oligosaccharide at position 8 in the HA stalk region. Thus, the H3N2 IAV acquired cleavability by an alternative HA activation mechanism/protease(s). Influenza A virus (IAV), a member of the Orthomyxoviridae family, affects and kills many humans worldwide. The viral hemagglutinin (HA) glycoprotein, which is responsible for receptor binding and subsequent membrane fusion, is synthesized as the inactive precursor, HA 0 , and cleaved by a host cell protease(s) into HA 1 and HA 2 subunits. The cleavage is essential for HA to mediate membrane fusion.Using mouse models, three research groups recently demonstrated that a type II transmembrane serine protease, TMPRSS2, expressed in the airway epithelium, is critically important for HA cleavage in vivo (1-3). Mice lacking TMPRSS2 expression (TMPRSS2 knockout [tmprss2 KO ] mice) are highly tolerant of challenge infection by low-pathogenic (LP) IAVs possessing a monobasic cleavage site in HA. Our group (1) and Hatesuer et al.(2) showed that TMPRSS2 is essential for proteolytic activation of both H1N1 and H3N2 subtype IAVs. However, Tarnow et al. (3) reported that TMPRSS2 is not critical for activation of H3N2 IAV. Since the three groups used different H3N2 IAV strains, the discrepancy likely arose from possible variations in HA among the H3N2 IAV strains. The present study reveals a molecular determinant that modulates the TMPRSS2 dependency of H3N2 IAV in mouse lungs.A mouse-adapted human H3N2 IAV strain, MA-A/Guizhou-X (H3 WT ) (1), was used as a reference wild-type (WT) virus. The virus was a reassortant H3N2 virus of A/Guizhou/54/89 (H3N2), a Chinese human isolate from 1989, and A/Puerto Rico/8/34 (H1N1) (4). The H3WT virus was passaged 10 times in tmprss2 KO mice, and a tmprss2 KO mouse-adapted MA-A/Guizhou-X virus ( H3 p10 ) was obtained.The parental H3 WT and H3 p10 viruses were inoculated intranasally into tmprss2 KO mice (n ϭ 5). After challenge infection with 3.0 ϫ 10 3 PFU of H3 WT , tmprss2 KO mice showed no body weight loss, while all TMPRSS2 ϩ/ϩ wild-type mice (tmprss2 WT ) showed severe body weight loss (Fig. 1A). Conversely, both tmprss2 KO and tmprss2 WT mice infected with 1.7 ϫ 10 2 PFU of H3 p10 showed severe body weight loss and required euthanasia on day 6 postinfection (p.i.) (Fig. 1B). To compare the susceptibility between the two mouse strains in detail, both mouse strains were also infected with 1.7 ϫ 10, 1.7, and 0.17 PFU of H3 p10 ( Fig. 1C to E). The H3 p10 infections exhibited pathogenicity in both tmprss2 KO and tmprss2 WT mice, although the pathological changes were slightly less severe in tmprss2 KO mice than in tmprss2 WT mice. The 50% lethal doses of H3 p10 for tmprss2 WT and tmprss2 KO mice w...

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TMPRSS2 Is a Host Factor That Is Essential for Pneumotropism and Pathogenicity of H7N9 Influenza A Virus in Mice

Cited by 131 publications

References 49 publications

Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs

In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

A Mutant H3N2 Influenza Virus Uses an Alternative Activation Mechanism in TMPRSS2 Knockout Mice by Loss of an Oligosaccharide in the Hemagglutinin Stalk Region

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