Interleukin (IL)-23 is a heterodimeric cytokine that shares the identical p40 subunit as IL-12 but exhibits a unique p19 subunit similar to IL-12 p35. IL-12/23 p40, interferon γ (IFN-γ), and IL-17 are critical for host defense against Klebsiella pneumoniae. In vitro, K. pneumoniae–pulsed dendritic cell culture supernatants elicit T cell IL-17 production in a IL-23–dependent manner. However, the importance of IL-23 during in vivo pulmonary challenge is unknown. We show that IL-12/23 p40–deficient mice are exquisitely sensitive to intrapulmonary K. pneumoniae inoculation and that IL-23 p19−/−, IL-17R−/−, and IL-12 p35−/− mice also show increased susceptibility to infection. p40−/− mice fail to generate pulmonary IFN-γ, IL-17, or IL-17F responses to infection, whereas p35−/− mice show normal IL-17 and IL-17F induction but reduced IFN-γ. Lung IL-17 and IL-17F production in p19−/− mice was dramatically reduced, and this strain showed substantial mortality from a sublethal dose of bacteria (103 CFU), despite normal IFN-γ induction. Administration of IL-17 restored bacterial control in p19−/− mice and to a lesser degree in p40−/− mice, suggesting an additional host defense requirement for IFN-γ in this strain. Together, these data demonstrate independent requirements for IL-12 and IL-23 in pulmonary host defense against K. pneumoniae, the former of which is required for IFN-γ expression and the latter of which is required for IL-17 production.

Local production of IL-17 is a significant factor in effective host defense against Gram-negative bacteria. However, the proximal events mediating IL-17 elaboration by T cells remain unclear. In this study, we show in vivo that intact Toll-like receptor 4 signaling in the lung is required for induction of both the p19 transcript of IL-23 and IL-17 protein elaboration in response to Klebsiella pneumoniae. Although IL-17 is widely considered a CD4+ T cell product, we also demonstrate significant in vitro IL-17 production by CD8+ T cells after culture in medium from dendritic cells exposed to these bacteria. The dominant portion of this IL-17-inducing activity for both CD4+ and CD8+ T cells is IL-23. These data demonstrate the critical signaling pathway for IL-17 induction in the host response to Gram-negative pulmonary infection and suggest a direct role for IL-23 in CD8+ T cell IL-17 production.

We investigated the role of interleukin-17 (IL-17)/IL-17 receptor (IL-17R)-mediated signaling in the protective immunity against Toxoplasma gondii. IL-17R؊/؊ mice developed a normal adaptive immunity against the parasite. However, increased mortality in the knockout animals can be attributed to a defect in the migration of polymorphonuclear leukocytes to infected sites during early infection.

Hospitalization of the elderly for invasive pneumococcal disease is frequently accompanied by the occurrence of an adverse cardiac event; these are primarily new or worsened heart failure and cardiac arrhythmia. Herein, we describe previously unrecognized microscopic lesions (microlesions) formed within the myocardium of mice, rhesus macaques, and humans during bacteremic Streptococcus pneumoniae infection. In mice, invasive pneumococcal disease (IPD) severity correlated with levels of serum troponin, a marker for cardiac damage, the development of aberrant cardiac electrophysiology, and the number and size of cardiac microlesions. Microlesions were prominent in the ventricles, vacuolar in appearance with extracellular pneumococci, and remarkable due to the absence of infiltrating immune cells. The pore-forming toxin pneumolysin was required for microlesion formation but Interleukin-1β was not detected at the microlesion site ruling out pneumolysin-mediated pyroptosis as a cause of cell death. Antibiotic treatment resulted in maturing of the lesions over one week with robust immune cell infiltration and collagen deposition suggestive of long-term cardiac scarring. Bacterial translocation into the heart tissue required the pneumococcal adhesin CbpA and the host ligands Laminin receptor (LR) and Platelet-activating factor receptor. Immunization of mice with a fusion construct of CbpA or the LR binding domain of CbpA with the pneumolysin toxoid L460D protected against microlesion formation. We conclude that microlesion formation may contribute to the acute and long-term adverse cardiac events seen in humans with IPD.

Host defense mechanisms against Pneumocystis carinii are not fully understood. Previous work in the murine model has shown that host defense against infection is critically dependent upon host CD4 ؉ T cells. The recently described Th17 immune response is predominantly a function of effector CD4 ؉ T cells stimulated by interleukin-23 (IL-23), but whether these cells are required for defense against P. carinii infection is unknown. We tested the hypothesis that P. carinii stimulates the early release of IL-23, leading to increases in IL-17 production and lung effector CD4 ؉ T-cell population that mediate clearance of infection. In vitro, stimulation of alveolar macrophages with P. carinii induced IL-23, and IL-23p19 mRNA was expressed in lungs of mice infected with this pathogen. To address the role of IL-23 in resistance to P. carinii, IL-23p19؊/؊ and wild-type control C57BL/6 mice were infected and their fungal burdens and cytokine/chemokine responses were compared. IL-23p19؊/؊ mice displayed transient but impaired clearance of infection, which was most apparent 2 weeks after inoculation. In confirmatory studies, the administration of either anti-IL-23p19 or anti-IL-17 neutralizing antibody to wild-type mice infected with P. carinii also caused increases in fungal burdens. IL-17 and the lymphocyte chemokines IP-10, MIG, MIP-1␣, MIP-1␤, and RANTES were decreased in the lungs of infected IL-23p19؊/؊ mice in comparison to their levels in the lungs of wild-type mice. In IL-23p19؊/؊ mice infected with P. carinii, there were fewer effector CD4 ؉ T cells in the lung tissue. Collectively, these studies indicate that the IL-23-IL-17 axis participates in host defense against P. carinii.

Bacterial pneumonia is the most common cause of lower respiratory tract infection in immunocompromised populations, including the alcohol-abusing patient. Furthermore, alcoholics are frequently infected with highly virulent respiratory pathogens and consequently experience increased morbidity and mortality from bacterial pneumonia. The resulting increase in health care resource use in these patients represents a significant public health concern. Host defense mechanisms are operant from the nasopharynx to the alveolus, many of which are adversely affected by excessive alcohol intake. Although the increased risk of oropharyngeal aspiration has been recognized for centuries, only recently have detailed studies of the mechanical, innate, and adaptive immune systems identified specific mechanisms throughout the aerodigestive tract whereby ethanol exposure renders the individual more susceptible to infection. In addition to directly inhibiting the ability of resident lung immune cells to kill bacteria, excessive ethanol use suppresses the normally protective acute inflammatory response to infection, resulting in the defective recruitment of additional innate immune cells. Additionally, ethanol disrupts the intricate interface that exists between innate and adaptive pulmonary immunity, further hindering the alcoholic host's ability efficiently to eliminate invading pathogens. Whether immunomodulatory therapies, designed to augment the immune response in such patients, will be effective adjunct therapy in such patients remains to be determined. This article reviews some of the key mechanisms of pulmonary host defense that are negatively impacted in the setting of alcohol abuse.

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Vulvovaginal candidiasis (VVC) caused by Candida albicans affects a significant number of women during their reproductive ages. Clinical observations revealed that a robust vaginal polymorphonuclear neutrophil (PMN) migration occurs in susceptible women, promoting pathological inflammation without affecting fungal burden. Evidence to date in the mouse model suggests that a similar acute PMN migration into the vagina is mediated by chemotactic S100A8 and S100A9 alarmins produced by vaginal epithelial cells in response to Candida. Based on the putative role for the Th17 response in mucosal candidiasis as well as S100 alarmin induction, this study aimed to determine whether the Th17 pathway plays a role in the S100 alarmin-mediated acute inflammation during VVC using the experimental mouse model. For this, IL-23p19−/−, IL-17RA−/− and IL-22−/− mice were intravaginally inoculated with Candida, and vaginal lavage fluids were evaluated for fungal burden, PMN infiltration, the presence of S100 alarmins and inflammatory cytokines and chemokines. Compared to wild-type mice, the cytokine-deficient mice showed comparative levels of vaginal fungal burden and PMN infiltration following inoculation. Likewise, inoculated mice of all strains with substantial PMN infiltration exhibited elevated levels of vaginal S100 alarmins in both vaginal epithelia and secretions in the vaginal lumen. Finally, cytokine analyses of vaginal lavage fluid from inoculated mice revealed equivalent expression profiles irrespective of the Th17 cytokine status or PMN response. These data suggest that the vaginal S100 alarmin response to Candida does not require the cells or cytokines of the Th17 lineage, and therefore, the immunopathogenic inflammatory response during VVC occurs independently of the Th17-pathway.