Life science
Medicine / Healthcare, Drug discovery

Elucidation of mechanism underlying exacerbation of bacterial pneumonia following influenza infection fordevelopment of preventive and therapeutic measures against superinfection
Department of Oral and Molecular Microbiology, Graduate School of Dentistry
Associate Professor Tomoko Sumitomo

Researchmap https://researchmap.jp/tomoko_sumitomo

Professor Shigetada Kawabata

Researchmap https://researchmap.jp/read0185239

Life science

Abstract
Influenza A virus (IAV) infection predisposes the host to secondary bacterial pneumonia, known as a major cause of morbidityand mortality during influenza epidemics. Although it is generally
accepted that preceding IAV infection leads to increased susceptibility to secondary bacterial infection, details regarding the pathogenic mechanism during the early stage of superinfection remain
elusive. Here, we focused on the interaction of IAV-infected cells
and Streptococcus pneumoniae, which revealed that human epithelial cells infected with IAV exhibit a cell-surface display of GP96,
an endoplasmic reticulum chaperon. Notably, extracellular GP96
was shown to impart efficient adherence for secondary infection byS. pneumoniae and GP96 inhibition ameliorated lung pathology ofsuperinfected mice, indicating it to be a useful target for development of therapeutic strategies for patients with superinfection.

sponses as well, during secondary bacterial pneumonia following
an influenza infection. Because of the complexity of the pathogenesis, a balanced combination of antimicrobial agents and immunomodulators could be more effective for prospective therapeutics.
We believe that GP96 is a potential target for development ofpromising therapeutic strategies, including combination therapies
as alternatives to conventional antibiotics and antiviral agents administered for broad-spectrum prevention, as well as managementof secondary bacterial infections following influenza.

▍ Background & Results
Secondary bacterial infections following a primary influenza virus
infection are frequent complications, and result in the majority ofrelated deaths during seasonal and pandemic influenza outbreaks.
S. pneumoniae is the most commonly identified pathogen in secondary bacterial pneumonia cases. Although antibiotics remain themainstay of therapy for affected patients, the increasing prevalenceof multidrug-resistant S. pneumoniae is a serious public health concern worldwide. Thus, development of host-directed therapeutics
is receiving focus as an alternative approach to treating secondary
bacterial pneumonia following influenza. Analysis of interactions
between IAV-infected human epithelial cells and Streptococcus
pneumoniae revealed that infected cells ectopically exhibited theendoplasmic reticulum chaperon GP96 on the surface. Importantly,
efficient pneumococcal adherence to epithelial cells was imparted
by interactions with extracellular GP96 and integrin αV, with thesurface expression mediated by GP96 chaperone activity (Fig. 1).
Furthermore, abrogation of adherence was gained by chemical
inhibition or genetic knockout of GP96. Direct binding of extracellular GP96 and pneumococci was shown to be mediated bypneumococcal oligopeptide permease components. Additionally,
IAV infection induced activation of calpains and Snail1, which areresponsible for degradation and transcriptional repression of junctional proteins in the host, respectively, indicating increased bacterial translocation across the epithelial barrier. Notably, treatment ofIAV-infected mice with the GP96 inhibitor enhanced pneumococcal
clearance from lung tissues and ameliorated lung pathology (Fig.
2).

Fig. 1. IAV infection-induced surface display of GP96 promotes pneumococcal
adherence to human alveolar epithelial cells.

Fig. 2. Lung tissues obtained mice were subjected to HE staining. Boxed area ismagnified and shown in lower panels. PU-WS13, GP96 inhibitor.

▍ Significance of the research and Future perspective
Our data indicate that GP96 functions as a multifunctional exacerbation factor to promote pneumococcal colonization, dysfunctionof lung tissue barrier, and probably dysregulation of immune re-Fig. 3. Mechanisms underlying exacerbation of bacterial pneumonia following
influenza infection.

P a t e n t
Sumitomo, Tomoko; Nakata, Masanobu; Kawabata Shigetada et al. GP96 drives exacerbation of secondary bacterial pneumonia following influenza Avirus infection. Mbio, 2021; 12(3): e0326920. doi: 10.1128/mBio.03269-20
https://resou.osaka-u.ac.jp/ja/research/2021/20210604_1
URL
https://web.dent.osaka-u.ac.jp/mcrbio/index.html
K e y w o r d influenza, streptococcus pneumoniae, pneumonia
Tr e a t i s e