Loss of T‐bet confers survival advantage to influenza–bacterial superinfection

Abstract

The transcription factor, T‐bet, regulates type 1 inflammatory responses against a range of infections. Here, we demonstrate a previously unaddressed role of T‐bet, to influenza virus and bacterial superinfection. Interestingly, we found that T‐bet deficiency did not adversely affect the efficacy of viral clearance or recovery compared to wild‐type hosts. Instead, increased infiltration of neutrophils and production of Th17 cytokines (IL‐17 and IL‐22), in lungs of influenza virus‐infected T‐bet−/− mice, were correlated with survival advantage against subsequent infection by Streptococcus pneumoniae. Neutralization of IL‐17, but not IL‐22, in T‐bet−/− mice increased pulmonary bacterial load, concomitant with decreased neutrophil infiltration and reduced survival of T‐bet−/− mice. IL‐17 production by CD8+, CD4+ and γδ T cell types was identified to contribute to this protection against bacterial superinfection. We further showed that neutrophil depletion in T‐bet−/− lungs increased pulmonary bacterial burden. These results thus indicate that despite the loss of T‐bet, immune defences required for influenza viral clearance are fully functional, which in turn enhances protective type 17 immune responses against lethal bacterial superinfections.

T-bet optimizes CD4 T-cell responses against influenza through CXCR3-dependent lung trafficking but not functional programming

“…T-bet-deficient mice retain the ability to clear even high doses of primary IAV infection as well as WT mice. These results are in agreement with a recent study 51 finding low-dose IAV-primed Tbx21 −/− mice are better protected against secondary bacterial infection than are WT animals. We extend these observations to show that IAV-primed Tbx21 −/− mice develop robust heterosubtypic immunity with no discemable defects compared to WT mice following supralethal IAV challenges.…”

Mice Deficient in T-bet Form Inducible NO Synthase–Positive Granulomas That Fail to Constrain Salmonella

“…Nevertheless, the induction of TNF-α appears insufficient to promote bacterial clearance. Augmented Th17 responses in T-bet −/− mice have been reported in other infectious models, with Francisella tularensis and influenza virus ( 52 , 53 ) with variable consequences on protection in these models. Because Th17 responses are linked to a neutrophilia within tissues, and that under some circumstances these cells can mediate tissue damage ( 54 ) and impair T cells responses ( 34 , 55 , 56 ), we hypothesized that aberrant Th17 responses could contribute to the failure to control Salmonella infection.…”

Dysregulation of Pulmonary Responses in Severe COVID-19

“…Interestingly, compared with mild cases, BALFs of severe cases had decreased TH17 [RAR-related orphan receptor C (RORC) + or C-C motif chemokine receptor 6 (CCR6) + ] cells ( Figure 1 A) and γδT (T cell receptor delta constant, or TRDC + ) cells ( Figure 1 B); the latter also express TH17-type cytokines, IL17, and IL17F (and TH1 type cytokine IFNγ). Although TH17 cells are considered as a potent mediator of tissue pathology, they are essential in antiviral immunity through promoting TH1, cytotoxic T lymphocyte, and B cell responses, and are implicated in combating concomitant bacterial (and maybe also fungal) infection [ 14 , 15 ]. The impaired TH17 responses in severe cases suggest a protective role of TH17-type cells, which further implicates the potential benefit of antibiotics (and maybe also antimycotics) for patients with severe disease.…”