Potential role for alternatively activated macrophages in the secondary bacterial infection during recovery from influenza

Abstract

Purpose Secondary bacterial infections are a common complication of influenza. Innate immune host defenses appear to be impaired following influenza, leading to susceptibility to subsequent bacterial infections. Alternatively activated macrophages (AAM) in the lungs may play a critical role in eliciting the hypersusceptibility to secondary bacterial pneumonia. Methods C57BL6 mice were challenged with sublethal doses of the mouse-adapted A/PR/8/34 (PR8) influenza virus or saline and allowed to recover. At complete recovery (day 14), mice were re-challenged with sublethal doses of Streptococcus pneumoniae serotype 3 (Sp3). Results PR8-recovered mice developed a rapidly fatal pulmonary infection to a 100-fold sublethal pneumococcal challenge, whereas PR8-naive mice demonstrated no mortality or illness. The cytokines which induce AAM (IL-4 and IL-13) and the expression of genes associated with AAM (Arginase-1, FIZZ1, and YM1) were elevated after PR8 infection. Flow cytometry suggests that alveolar macrophages demonstrate the AAM-phenotype, as indicated by MGL-1 and MHCII expression, in response to PR8 infection. Recovery from PR8 was associated with blunted cytokine responses to TLR ligands. Conclusions The mechanisms of immune regulation during recovery from influenza are being elucidated. We provide evidence that pulmonary AAM are induced during influenza infection and may contribute to the elicitation of hypersusceptibility to a secondary bacterial infection.

Antiviral Regulation in Porcine Monocytic Cells at Different Activation States

“…Because viruses such as HIV and RSV altered activation statuses in macrophages (16)(17)(18)(19), we examined whether PRRSV infection interacts differentially with macrophages at different activation statuses. PRRSV infection induced differential cytokine responses in Ms polarized with different mediators (Fig.…”

“…Our studies here integrate antiviral regulation into the paradigm of activation statuses in porcine monocytic cells, a group of immune cells that not only are critical for overall immune responses but also are targeted by numerous economically devastating viruses to evade antiviral immunity (16)(17)(18)(19)21). These monocytotropic viruses include many of the world's most dreaded porcine viruses, such as African swine fever virus (ASFV), classical swine fever virus (CSFV), porcine circovirus 2 (PCV2), foot-and-mouth disease virus (FMDV), pseudorabies virus (PrV), swine influenza virus (SIV), and the focus of our studies, PRRSV (19,21,24,36).…”

“…For example, HIV and respiratory syncytial virus (RSV) were shown to alter M activation statuses, thus affecting viral pathogenesis and host immune responses (16)(17)(18). In addition, most pandemic viral infections cause disease syndromes frequently complicated with coinfection from pathogens of other phyla (19)(20)(21)(22)(23). Thus, it is important to integrate the activation status with antiviral states linked to type I IFN production and action (16)(17)(18)(19).…”

“…In addition, most pandemic viral infections cause disease syndromes frequently complicated with coinfection from pathogens of other phyla (19)(20)(21)(22)(23). Thus, it is important to integrate the activation status with antiviral states linked to type I IFN production and action (16)(17)(18)(19). Understanding the relationships among activation statuses and antiviral states not only extends the activation paradigm of monocytic cells but also integrates antiviral regulation into the scenario of immune responses, including inflammation, tissue repair, and overall antimicrobial activity (11,17,18,21).…”

Arginase 1 activity worsens lung‐protective immunity against Streptococcus pneumoniae infection

“…This pathway of infectioninduced Arg1 expression in the lung myeloid cell compartment was also observed in the current study in response to Spn, where we observed an infection dose dependent increase in Arg1 mRNA and protein levels in Spn-infected mice. On the other hand, Arg1-expressing alternatively activated macrophages have recently been shown to limit the severity of influenza infection in mice previously colonized with Spn [29], and the virulence factor Ply of Spn has been implicated in the generation of Arg1-expressing alternatively activated macrophages [30]. In this report, Spn-induced Arg1 expression, which was particularly observed in exudate rather than alveolar macrophages, did not impair lung antibacterial immunity against Spn, as Spn-infected WT mice had similar bacterial loads in their lungs as compared to Spn-infected conditional Arg1 KO mice.…”