Bacterial flagellin promotes viral entry via an NF-kB and Toll Like Receptor 5 dependent pathway

Abstract

Viruses and bacteria colonize hosts by invading epithelial barriers. Recent studies have shown that interactions between the microbiota, pathogens and the host can potentiate infection through poorly understood mechanisms. Here, we investigated whether diverse bacterial species could modulate virus internalization into host cells, often a rate-limiting step in establishing infections. Lentiviral pseudoviruses expressing influenza, measles, Ebola, Lassa or vesicular stomatitis virus envelope glycoproteins enabled us to study entry of viruses that exploit diverse internalization pathways. Salmonella Typhimurium, Escherichia coli and Pseudomonas aeruginosa significantly increased viral uptake, even at low bacterial frequencies. This did not require bacterial contact with or invasion of host cells. Studies determined that the bacterial antigen responsible for this pro-viral activity was the Toll-Like Receptor 5 (TLR5) agonist flagellin. Exposure to flagellin increased virus attachment to epithelial cells in a temperature-dependent manner via TLR5-dependent activation of NF-ΚB. Importantly, this phenotype was both long lasting and detectable at low multiplicities of infection. Flagellin is shed from bacteria and our studies uncover a new bystander role for this protein in regulating virus entry. This highlights a new aspect of viral-bacterial interplay with significant implications for our understanding of polymicrobial-associated pathogenesis.

Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease

“…While modulation of TLR5 signaling via flagellin and regulation of neutrophilic immune responses via DNase I represent new avenues to fight against COVID-19, there are some potential risks as expected with any therapeutic approach. Exposure of flagellin has been reported to support lentiviral pseudovirus attachment on lung epithelial cells via TLR5 activation of NF-B signaling (6). Hence, it is plausible that TLR5 signaling could advance SARS-CoV-2 virulence, and TLR5-mediated proinflammatory responses could inflict unwarranted damage.…”

The Role of Innate Immunity in Pulmonary Infections

“…In rodents, TLR5 is critical for mucosal intrinsic defense activity of Salmonella enterica , P. aeruginosa , S. pneumoniae , and uropathogenic E. coli [ 150 , 151 ]. After bacterial recognition, plasma membrane-bound TLR5 recruits MyD88, followed by activation of NF- κ B through IRAKs, TRAF6, TAK1, and I κ B kinase (IKK) complexes to induce expression of inflammatory cytokines and chemokine gene, such as IL-8, IL-6, TNF- α , CXCL1, CXCL2, and CCL20 [ 152 – 155 ] ( Figure 1 ).…”

Microbiota and Its Role on Viral Evasion: Is It With Us or Against Us?

“…Recently, it was reported that bacterial flagellin promotes viral infection in an in vitro model using lentiviral pseudoviruses encoding the glycoproteins of influenza, Measles, Ebola, Lassa, and Vesicular stomatitis virus in pulmonary epithelial cell culture through TLR5 and NF-κB activation (Benedikz et al, 2019). This finding is particularly exciting since previously, it was reported that flagellin had a protective effect against RV infection in mice (Zhang et al, 2014).…”