Murine Type III interferons are functionally redundant and correlate with bacterial burden during influenza/bacterial super-infection

Abstract

Background Type III interferon, or interferon lambda (IFNλ) is a crucial antiviral cytokine induced by influenza infection. While IFNλ is important for anti-viral host defense, published data demonstrate that IFNλ is pathogenic during influenza/bacterial super-infection. It is known that polymorphisms in specific IFNλ genes affect influenza responses, but the effect of IFNλ subtypes on bacterial super-infection is unknown. Methods Using an established model of influenza, Staphylococcus aureus super-infection, we studied IFNλ3-/- and control mice to model a physiologically relevant reduction in IFNλ and to address its role in super-infection. Results Surprisingly, IFNλ3-/- mice did not have significantly lower total IFNλ than co-housed controls, and displayed no change in viral or bacterial clearance. Importantly, both control and IFNλ3-/- mice displayed a positive correlation between viral burden and total IFNλ in the bronchoalveolar lavage during influenza/bacterial super-infection, suggesting that higher influenza viral burden drives a similar total IFNλ response regardless of IFNλ3 gene integrity. Interestingly, total IFNλ levels positively correlated with bacterial burden, while viral burden and bronchoalveolar lavage cellularity did not. Conclusions These data suggest IFNλ2 can compensate for IFNλ3 to mount an effective antiviral and defense, revealing a functional redundancy in these highly similar IFNλ subtypes. Further, the IFNλ response to influenza, as opposed to changes in cellular inflammation or viral load, significantly correlates with susceptibility to bacterial super-infection. Moreover, the IFNλ response is regulated and involves redundant subtypes, suggesting it is of high importance to pulmonary pathogen defense.

Heterotypic Influenza Infections Mitigate Susceptibility to Secondary Bacterial Infection

“…Studies examining the role of interferons during bacterial super-infection have shown that they enhance susceptibility. The mechanisms highlighted in these studies are due to decreased Type 17 immune activation and destabilization in function and recruitment of phagocytic cells (10, 11, 14, 17, 39, 53, 54). Our data suggests that at the time of super-infection, influenza memory experienced mice have reduced levels in expression of interferons, which based on prior studies would indicate that anti-bacterial mechanisms are preserved.…”

Interferon Lambda: An Anonymous Warrior of Host-Microbial Fray in The Pathogenesis of Periodontal Diseases

“…12,13 Furthermore, IFN-λs has an impact on immune cells in response to viral infection by limiting viral replication, lowering viral load, and delaying the development of viral drug resistance, resulting in the development of antiviral immunity. [14][15][16][17][18][19][20][21] Due to the scarcity of researches, the precise involvement of IFN-λs in non-viral inflammatory conditions is yet be precisely investigated. IFN-λs are primarily expressed by epithelial cells, but myeloid cells, neutrophils, B lymphocytes, and dendritic cells have also been found to express IFN-λs.…”

IFNλ: balancing the light and dark side in pulmonary infection

“…While multiple studies have shown that IFNλ increases the severity of super-infection, the specific mechanism by which this occurs is still being elucidated ( 11 , 74 , 76 , 77 ). IFNλ treatment during super-infection was shown to reduce neutrophil recruitment to the airways and neutrophil phagocytosis of both S. pneumoniae and S. aureus .…”

“…IFNλ treatment during super-infection was shown to reduce neutrophil recruitment to the airways and neutrophil phagocytosis of both S. pneumoniae and S. aureus . Further, IFNλ levels in BAL fluid of super-infected mice correlate positively with the bacterial burden ( 11 , 76 ). However, the influence of IFNλ on antimicrobial peptide (AMP) production is controversial: studies have been published showing no effect on AMP production after an IFNλ treatment and that IFNλR1 knockout mice have increased levels of several AMPs, including regenerating family member III gamma and neutrophil gelatinase associated lipocalin ( 76 , 77 ).…”

“…It is possible that enhanced IFNλ3 antiviral activity could be caused by minor allele single-nucleotide polymorphisms (SNPs), which are known to cause increased responsiveness to influenza vaccination ( 10 ). However, one study showed that IFNλ2 and IFNλ3 can compensate for one another during murine pulmonary infections by selective deletion of IFNλ3 ( 11 ). Additional study of IFNλ subtypes is required to understand their common and distinct functions during infection to enhance the relevance of murine studies to the human population, as the use of IFNλ3 in mice may result in stronger phenotypes than what is seen with IFNλ1 in humans.…”