Keywords
Influenza, Interferons, Streptococcus Pneumoniae, SPn co-infection, IFN-γ
Commentary
Influenza A virus (IAV) and Streptococcus pneumoniae (SPn) are two major respiratory pathogens in humans. IAV infection alone is often self-limited, and SPn colonization can be found in 5-90% of healthy individuals, as normal flora [1,2]. On the other hand, IAV and SPn co-infection represents a major health concern and is known to cause severe morbidity and mortality in influenza pandemics and epidemics [3-6]. The murine models of IAV and bacterial co-infection are well-established and replicate key characteristics of human patients. Multiple mechanisms have been revealed to be involved in co-pathogenesis, including enhanced bacterial colonization and invasion, suppression of antimicrobial immunity, and acute lung injury. It is likely that these pathogenic mechanisms concomitantly or sequentially promote co-infection progression [7]. Here we will discuss some recent evidence on the role and interplay between type I IFNs (IFN-I), i.e., IFN-α/β, and IFN-g in promoting IAV/SPn co-pathogenesis.
Acute respiratory viral infection typically activates IFN responses in the lung. These IFNs are critical regulators of the balance between antiviral immunity and detrimental inflammation [8,9]. Alveolar macrophages are the main producers of IFN-I at the early stage of IAV infection [10,11]. IFN-I signaling not only limits virus replication but also attenuates inflammatory lung damage [12-14]. Nonetheless, T cell recruitment and activation at the later phase (~7 d) is essential to clear IAV infection. Influenza typically activates IFN-g-biased cytokine production by T cells [8]. IFN-γ is not required for viral clearance but limits lung inflammation [15]. Notably, influenza-induced peak susceptibility to SPn infection coincides with T cell recruitment [16]. Furthermore, T cell depletion restores acute bacterial clearance after IAV/SPn co-infection [17], suggesting a key role of T cells in suppression of innate antibacterial immunity [16,18].
Conversely, immune clearance of SPn infection requires phagocytic cells. Resident alveolar macrophages represent a strong first line of innate defense against extracellular bacteria [19,20], explaining the unproblematic SPn carriage in healthy individuals. Neutrophils play a significant role in bacterial killing especially at the later stage of infection. Recent evidence indicates that the antibacterial function of both alveolar macrophages and neutrophils is impaired by IAV-induced IFN responses, particularly IFN-γ and IFN-I, [21-27], thereby predisposing hosts to secondary bacterial pneumonia.
Compelling evidence from animal models indicates that IAV infection induces alveolar macrophage dysfunction and depletion [16,28-31]. Specifically, we have shown that T cell-derived IFN-γ inhibits alveolar macrophage-mediated bacterial killing during recovery from IAV infection [16]. In agreement, a mathematical model predicts that alveolar macrophage dysfunction is primarily responsible for bacterial outgrowth during co-infection [32]. It has also been shown in BALB/c mice that IAV infection depletes alveolar macrophages [28]. However, the effect of IAV infection on alveolar macrophage survival appears to be dependent on viral virulence and mouse genetic strains. As such, alveolar macrophage levels are maintained after a low dose of A/PR/8 (H1N1) infection in C57BL/6 mice and throughout the course of low-virulent X31 (H3N2) infection in BALB/c mice. Conversely, using both IFN-γ gene-deficient mice as well as in vivo neutralizing antibodies, we have recently demonstrated that IFN-γ induces alveolar macrophage depletion during co-infection progression. Collectively, these findings indicate that IFN-γ not only impairs alveolar macrophage antibacterial function but also their viability during the co-pathogenesis process.
On the other hand, IFN-I signaling promotes inflammatory monocyte recruitment after IAV infection. Monocytes are normally protective against SPn infection alone [33], but their inflammatory property is detrimental to antibacterial defense after IAV infection [34-36], by promoting IFN-I [37] and IFN-g-induced lung epithelial damage [36]. Of particular interest, during recovery from IAV infection, these CCR2-recruited monocytes differentiate into alveolar macrophages to confer prolonged antibacterial protection [38]. The mechanism underlying the phenotypic and functional transition of monocytes remains unclear.
Another common observation during IAV and bacterial co-infection is neutrophil dysregulation [39,40]. As the first responders to microbial infections, neutrophils perform a critical role in host defense against opportunistic pathogens, and their prompt recruitment is crucial to prevent the establishment of infection. In line with that, multiple studies have demonstrated that IAV-induced IFN-I response suppresses neutrophil recruitment and thereby increases host susceptibility to pneumococcal pneumonia [18,22,26,41]. In addition to that, IFN-g signaling also suppresses neutrophil infiltration [17,42]. However, neutrophilic inflammation increases acute lung damage, which can inadvertently exacerbate disease progression [43,44].
Unlike other high-virulent mouse-adapted IAV strains, X31 infection alone does not induce strong IFN-g response. We have recently reported that prior X31 infection induces lethal susceptibility to SPn pneumonia in C57BL/6 but not BALB/c mice. In line with that, X31/SPn co-infection induces prominent IFN-g production in C57BL/6 mice and thereby promotes the hypersusceptibility. Interestingly, the resistant BALB/c mice depend on neutrophils for effective bacterial clearance. In fact, C57BL/6 mice exhibited significantly increased neutrophil infiltration than BALB/c animals, but they were still defective in lung bacterial control. It suggests that IFN-γ may play a role in inhibiting neutrophil function. Indeed, IAV infection has been shown to impair neutrophil antibacterial function [40]. Thus, IFN-γ can play multiple roles in innate suppression during IAV/SPn co-pathogenesis, including impairment of AM function and survival [16,30], inhibition of neutrophil recruitment, and likely neutrophil dysfunction.
During IAV infection alone, it has been shown that rather than regulating IFN-γ production, IFN-I reduces IFN-γR expression and thereby protects Ly6Clo monocytes/macrophages from IFN-γ-induced activation [8]. IFN-I also promotes SPn colonization and transmission following secondary IAV infection [45,46]. Using a similar SPn carriage model, it has been demonstrated that sequential neutralization of IFN-I and IFN-γ pathways provides optimal protection against SPn/IAV co-infection [47]. In agreement with that, we have shown that IFN-I signaling plays a significant role in suppression of acute bacterial clearance. However, IFN-I signaling is essential for preventing IFN-γ hyperproduction and subsequent exacerbation of co-infection. Of note, the susceptibility to secondary bacterial pneumonia peaks around a week after IAV infection, coinciding with T cell IFN-g production [16]. A similar time interval has been observed between the onset of symptoms of viral infection and bacterial pneumonia in humans [48]. Thus, it is likely the IFN-γ plays a dominant role in immune predisposition to SPn superinfection, particularly during recovery from viral infection (Figure 1).
Figure 1: IFN-I and IFN-g in IAV and SPn co-pathogenesis. At the innate phase of IAV infection, alveolar macrophages produce IFN-I to limit viral replication. IFN-I signaling recruits monocytes and limits neutrophil infiltration, resulting in impaired innate defense against SPn infection. At the adaptive phase of influenza, T cells are recruited to clear viruses in the lung. However, T cell-derived IFN-g impairs the antibacterial function of both alveolar macrophages and neutrophils, thereby perpetuating host susceptibility to bacterial pneumonia after influenza. Created with Biorender.com.
In summary, recent evidence indicates that during the early phase of IAV infection, IFN-I plays a key role in suppression of antibacterial immunity by inhibiting neutrophil recruitment; while at the recovery phase of IAV infection, T cell-derived IFN-γ plays a dominant role in suppression of both alveolar macrophages and neutrophils. The sequential IFN-I and IFN-γ signaling results in the prolonged host susceptibility to pneumococcal infection after influenza.
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