Influenza A virus impairs control of Mycobacterium tuberculosis coinfection through a type I interferon receptor-dependent pathway

Abstract

Influenza followed by severe acute bacterial pneumonia is a major cause of mortality worldwide. Several mechanisms account for this enhanced susceptibility, including increased production of type I interferon (IFN). In individuals infected with Mycobacterium tuberculosis, the influence of acute viral infections on tuberculosis progression is unclear. We show that prior exposure of mice to influenza A virus, followed by M. tuberculosis infection, leads to enhanced mycobacterial growth and decreased survival. Following M. tuberculosis/influenza virus coinfection, mycobacterial growth is enhanced by a type I IFN signaling pathway. Our findings highlight the detrimental influence influenza virus infection can have before or during M. tuberculosis infection.

Keywords: Interferon; Mycobacterium tuberculosis; co-infection; influenza; tuberculosis; type I IFN.

Figure 1.

Prior exposure to influenza A virus (IAV) predisposes mice to enhanced susceptibility to subsequent Mycobacterium tuberculosis infection. Mice were first infected intranasally with IAV subtypes X31 (median tissue culture infective dose [TCID₅₀] of 1 × 10⁴; A) or PR8 (TCID₅₀ of 100; B–E) or were mock infected with phosphate-buffered saline. A total of 28 days later, mice were challenged via aerosol with M. tuberculosis, and the numbers of viable mycobacteria in the lungs were determined at the time points indicated. The extent of inflammation in the lungs (D) and survival (E) following M. tuberculosis infection was also monitored in animals (8–10 mice per group) that had or had not been previously infected with IAV subtype PR8. Results shown are representative of at least 2 independent experiments, with individual data points depicting individual mice. Statistically significant differences in the numbers of viable mycobacteria in the lungs between groups were assessed using the Mann–Whitney U test, with the resulting P values indicated. The differences in survival between control and coinfected mice were determined by the log-rank test, with the resulting P value indicated.

Figure 2.

Concurrent influenza A virus (IAV) challenge impairs Mycobacterium tuberculosis control by a mechanism dependent on type I interferon (IFN) signaling. Mice were first infected via aerosol with M. tuberculosis and then were intranasally challenged with IAV (or were mock infected with phosphate-buffered saline) on day 1 (Cal/09; [TCID₅₀] of 1 × 10⁴) and day 14 (X31; TCID₅₀ of 2.4 × 10⁴) after M. tuberculosis infection. Mice were killed on day 27 after M. tuberculosis infection, and the numbers of viable mycobacteria in the lungs were determined. Results shown are representative of 2 independent experiments, with individual data points depicting individual mice. Statistical comparisons were performed using 1-way analysis of variance with a Bonferroni multiple comparison posttest. *P < .05. IFNαβR ^–/–, C57Bl/6 × Ifnar1^−/− mice; Abbreviations: NS, nonsignificant; WT, wild-type mice.