Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics

Garten, Wolfgang; Braden, Carolin; Arendt, A; Peitsch, Catharina; Baron, Joanna; Lu, Yinghui; Pawletko, Kerstin; Hardes, Kornelia; Steinmetzer, Torsten; Böttcher‐Friebertshäuser, Eva

doi:10.1016/j.ejcb.2015.05.013

Cited by 76 publications

(72 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 96%

In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

Pászti-Gere

Czimmermann

Ujhelyi

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 96%

In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

Pászti-Gere

Czimmermann

Ujhelyi

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Human and swine IAV (swIAV) preferentially bind to α2,6-linked sialic acid, whereas most avian IAV have a preference for α2,3-linked sialic acid9. To enter host cells by fusion of the viral and the cellular membrane, the haemagglutinins of mammalian IAV are activated in the respiratory tract by proteases like TMPRSS2 and HAT10.…”

mentioning

confidence: 99%

The differentiated airway epithelium infected by influenza viruses maintains the barrier function despite a dramatic loss of ciliated cells

Yang

Beineke³

et al. 2016

Sci Rep

108

View full text Add to dashboard Cite

Virus-host interactions in the respiratory epithelium during long term influenza virus infection are not well characterized. Therefore, we developed an air-liquid interface culture system for differentiated porcine respiratory epithelial cells to study the effect of virus-induced cellular damage. In our well-differentiated cells, α2,6-linked sialic acid is predominantly expressed on the apical surface and the basal cells mainly express α2,3-linked sialic acid. During the whole infection period, release of infectious virus was maintained at a high titre for more than seven days. The infected epithelial cells were subject to apoptosis resulting in the loss of ciliated cells together with a thinner thickness. Nevertheless, the airway epithelium maintained trans-epithelial electrical resistance and retained its barrier function. The loss of ciliated cells was compensated by the cells which contained the KRT5 basal cell marker but were not yet differentiated into ciliated cells. These specialized cells showed an increase of α2,3-linked sialic acid on the apical surface. In sum, our results help to explain the localized infection of the airway epithelium by influenza viruses. The impairment of mucociliary clearance in the epithelial cells provides an explanation why prior viral infection renders the host more susceptible to secondary co-infection by another pathogen.

show abstract

“…The HA of avian influenza viruses with a polybasic cleavage site is known to be cleaved intracellularly by furin. Recently, it was demonstrated that the HA of human H1N1 viruses is also cleaved intracellularly by TMPRSS2 protease (reviewed in [50]). It was shown that the acid sensitive HA of the (H1N1)pdm09 virus is in the same way protected from the premature conformational changes during intracellular transport by the M2 ion channel [51].…”

Section: Discussionmentioning

confidence: 99%

Factors affecting the immunogenicity of the live attenuated influenza vaccine produced in continuous cell line

Wolkerstorfer

Katinger

Romanova

2016

Microbiology Independent Research Journal (MIR Journal)

View full text Add to dashboard Cite

The biological basis for the restricted immunogenicity of some live attenuated influenza vaccine strains generated on the backbone of the cold adapted (ca) A/Singapore/1/1957/ca (H2N2) influenza A virus master strain and produced in the Vero cells was investigated. According to our previous results the vaccine candidate made from A/Hong Kong/1035/1998 (H1N1) Vero-derived virus did not provoke a measurable antibody titers following the intranasal immunization of humans. We report here that the hemagglutinin (HA) of A/Hong Kong/1035/1998 virus contained the mutation 10Ile→Val in the HA2 subunit, that increased the pH threshold of HA conformational change (pH of activation) by 0.3 pH units and therefore might be responsible for the lack of immune response in humans. Similar effect was shown for the reassortant made from the Vero-derived A/Switzerland/5389/1995 (H1N1) (5389wt) virus which had the HA2 mutation 3Phe→Leu leading to the lack of immune response in mice. Another factor compromising the immunogenicity of a vaccine candidate is the incompatibility of epidemic virus HA with the M gene of the master strain. In mice the 6/2 A/Switzerland/5389/1995 reassortant induced antibodies that were directed predominantly to the HA2 subunit and were detectable by ELISA but not by a hemagglutination inhibition (HAI) test. In contrast, the 5/3 reassortant, bearing the HA, neuraminidase (NA), and M genes from the epidemic virus induced an equivalent amount of antibodies against the HA1 and HA2 subunits detected by HAI and ELISA. By comparing the sensitivity of the viruses to amantadine, we showed that the M2 ion channel of the master strain had lower activity than that of the A/Switzerland/5389/1995. These data suggest that M2 of the master strain was not sufficiently active to keep the pH of the transGolgi network high enough to prevent the conformational change of the acid sensitive HA to the low pH form.Overall, the adaptation mutations in the HA of the vaccine candidate that increase the pH of HA activation as well as the incompatibility of HA and M genes must be taken into consideration when constructing the reassortant strains for the live attenuated vaccine.

show abstract

Influenza virus activating host proteases: Identification, localization and inhibitors as potential therapeutics

Cited by 76 publications

References 57 publications

In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

The differentiated airway epithelium infected by influenza viruses maintains the barrier function despite a dramatic loss of ciliated cells

Factors affecting the immunogenicity of the live attenuated influenza vaccine produced in continuous cell line

Contact Info

Product

Resources

About