Sequential targeting of interferon pathways for increased host resistance to bacterial superinfection during influenza

Abstract

Bacterial co-infections represent a major clinical complication of influenza. Host-derived interferon (IFN) increases susceptibility to bacterial infections following influenza, but the relative roles of type-I versus type-II IFN remain poorly understood. We have used novel mouse models of co-infection in which colonizing pneumococci were inoculated into the upper respiratory tract; subsequent sublethal influenza virus infection caused the bacteria to enter the lungs and mediate lethal disease. Compared to wild-type mice or mice deficient in only one pathway, mice lacking both IFN pathways demonstrated the least amount of lung tissue damage and mortality following pneumococcal-influenza virus superinfection. Therapeutic neutralization of both type-I and type-II IFN pathways similarly provided optimal protection to co-infected wild-type mice. The most effective treatment regimen was staggered neutralization of the type-I IFN pathway early during co-infection combined with later neutralization of type-II IFN, which was consistent with the expression and reported activities of these IFNs during superinfection. These results are the first to directly compare the activities of type-I and type-II IFN during superinfection and provide new insights into potential host-directed targets for treatment of secondary bacterial infections during influenza.

Disease Tolerance during Viral-Bacterial Co-Infections

“…Type-II IFN elaborated later in the IAV infection process alters the function and phagocytosis capacity of AM, which then fuels the growth of bacteria and uncontrolled tissue damage [43,50,90]. The continual replication of bacteria results in recruitment of inflammatory cells to the lung and weakens the repair process [50,90,91]. These results implicate host IFN responses during IAV infection in enhancement of secondary bacterial infection.…”

“…Others have instead defined a critical role of type II IFN [39,40,[47][48][49] and direct inhibition of AM-mediated bacterial clearance. In our recent study we observed that influenza co-infection caused IFN-dependent inflammation that facilitated spreading of the colonizing bacteria into the lungs, followed by tissue damage and death [50]. Understanding the pathways responsible for co-infection during influenza has been complicated by several confounding factors.…”

“…Parasitic helminth infection/Trichuris muris in mice AREG Clearance of parasites and tissue healing, suppression of inflammation [63][64][65][66] Enteric infection with Shigella, E. coli, Helicobacter, Neisseria in human tissue AREG Healing by transcriptional upregulation [67][68][69][70] IAV infection in mice IL-5 Tissue integrity and host resistance [71,72] IAV-bacterial co-infection in mice IL-22 Reduction in inflammation, tissue integrity, induce tolerance [73,74] IAV infection in mice IL-22 Regeneration and repair of tissue [75,76] Ulcerative colitis in mice IL-22 Regeneration and repair of tissue [77] IAV infection in mice TGF-β Attenuation of lung inflammation [78,79] Hyperoxic lung injury in mouse and rats TGF-β Epithelial repair [80,81] IAV infection in acute asthmatic mice TGF-β Suppression of tissue injury [82] Tuberculosis infection in mice Lactoferrin Reduce immunopathology [83][84][85] Pseudomonas aeruginosa lung infection Lactoferrin Tissue integrity [86][87][88] LPS-induced lung injury Lactoferrin Tissue integrity [89] Viral-bacterial co-infection in mice IFNs Tissue damage in the airways [40,[43][44][45][46]50,[90][91][92] 3.1. Amphiregulin (AREG)…”

“…The rapid replication of IAV in the lung epithelium leads to cell damage and exposure of the basement membrane, causing loss of barrier function that subsequently facilitates bacterial spread. Type-II IFN elaborated later in the IAV infection process alters the function and phagocytosis capacity of AM, which then fuels the growth of bacteria and uncontrolled tissue damage [43,50,90]. The continual replication of bacteria results in recruitment of inflammatory cells to the lung and weakens the repair process [50,90,91].…”

Immune-mediated attenuation of influenza illness after infection: opportunities and challenges

“…72 Influenza infection might also impair regulatory mechanisms of innate and adaptive immune systems that do not suppress bacterial growth and promote superinfection. 135,136 Influenza infection-mediated breakdown in the lung barrier function increases risk of bacterial coinfection, but co-infections might also occur with milder disease pathology triggering host cytokine pathways. Thus, if milder infections also promote bacterial pneumonia without direct lung damage, the chances of attenuating bacterial pneumonia are less likely without blocking infection.…”