S100A9 is indispensable for survival of pneumococcal pneumonia in mice

S100A8/A9 has important immunomodulatory roles in antibacterial defense, but its relevance in focal pneumonia caused by Streptococcus pneumoniae (S. pneumoniae) is understudied. We show that S100A9 was significantly increased in BAL fluids of patients with bacterial but not viral pneumonia and correlated with procalcitonin and sequential organ failure assessment scores. Mice deficient in S100A9 exhibited drastically elevated Zn$^{2+}$ levels in lungs, which led to bacterial outgrowth and significantly reduced survival. In addition, reduced survival of S100A9 KO mice was characterized by excessive release of neutrophil elastase, which resulted in degradation of opsonophagocytically important collectins surfactant proteins A and D. All of these features were attenuated in S. pneumoniae-challenged chimeric WT→S100A9 KO mice. Similarly, therapy of S. pneumoniae-infected S100A9 KO mice with a mutant S100A8/A9 protein showing increased half-life significantly decreased lung bacterial loads and lung injury. Collectively, S100A9 controls central antibacterial immune mechanisms of the lung with essential relevance to survival of pneumococcal pneumonia. Moreover, S100A9 appears to be a promising biomarker to distinguish patients with bacterial from those with viral pneumonia. Trial registration: Clinical Trials register (DRKS00000620)

Human seroreactivity to gut microbiota antigens

Background: Although immune responses directed against antigens from the intestinal microbiota are observed in certain diseases, the normal human adaptive immune response to intestinal microbiota is poorly defined. Objective: Our goal was to assess the adaptive immune response to the intestinal microbiota present in 143 healthy adults and compare this response with the response observed in 52 children and their mothers at risk of having allergic disease. Methods: Human serum was collected from adults and children followed from birth to 7 years of age, and the serum IgG response to a panel of intestinal microbiota antigens was assessed by using a novel protein microarray. Results: Nearly every subject tested, regardless of health status, had serum IgG that recognized a common set of antigens. Seroreactivity to the panel of antigens was significantly lower in atopic adults. Healthy infants expressed the highest level of IgG seroreactivity to intestinal microbiota antigens. This adaptive response developed between 6 and 12 months of age and peaked around 2 years of age. Low IgG responses to certain clusters of microbiota antigens during infancy were associated with allergy development during childhood. Conclusions: There is an observed perturbation of the adaptive response to antigens from the microbiota in allergic subjects. These perturbations are observable even in childhood, suggesting that optimal stimulation of the adaptive immune system by the microbiota might be needed to prevent certain immune-mediated diseases.Funding Agencies|National Institutes of Health [DK071176]; Swedish Research Council [K2011-56X-21854-01-06]; Swedish Heart-Lung Foundation [20050514]; Ekhaga Foundation [210-53]; Research Council for the South-East Sweden; Olle Engqvist Foundation; Swedish Asthma and Allergy Association; Vardal Foundation for Health Care Science and Allergy Research, Sweden [B2007 042]; University Hospital of Linkoping, Sweden</p

Dysregulation of Systemic and Mucosal Humoral Responses to Microbial and Food Antigens as a Factor Contributing to Microbial Translocation and Chronic Inflammation in HIV-1 Infection

<div><p>HIV-1 infection is associated with an early and profound depletion of mucosal memory CD4⁺ T cells, a population that plays an indispensable role in the regulation of isotype switching and transepithelial transport of antibodies. In this study, we addressed whether the depletion of CD4⁺ T cell in HIV-1-infected individuals results in altered humoral responses specific to antigens encountered at mucosal surfaces. Comprehensive protein microarray of systemic humoral responses to intestinal microbiota demonstrated reduced IgG responses to antigens derived from Proteobacteria and Firmicutes but not Bacteroidetes. Importantly, intestinal secretions of antiretroviral therapy-treated HIV-1-infected individuals exhibited a significant elevation of IgM levels and decreased IgA/IgM and IgG/IgM ratios of antibodies specific to a variety of microbial and food antigens. The presented findings indicate reduced competence of mucosal B cells for class switch recombination from IgM to other isotypes limiting their capacity to react to changing antigenic variety in the gut lumen. Decreased availability of microbiota-specific IgA and IgG may be an important factor contributing to the translocation of microbial antigens across the intestinal mucosal barrier and their systemic dissemination that drives chronic inflammation in HIV-1-infected individuals.</p></div

Dysregulation of systemic and mucosal humoral responses to microbial antigens in HIV-1-infected individuals.

<p>Depletion of CD4⁺ T cells in the intestinal mucosa of HIV-1-infected individuals reduces the capacity of mucosal B cells to undergo class switch recombination resulting in an increased production of IgM. Accumulated microbiota-specific IgM may exacerbate inflammatory processes by the formation of inflammatory immune complexes [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006087#ppat.1006087.ref028" target="_blank">28</a>]. Epithelial cell apoptosis and decreased availability of antigen-specific IgG and IgA in mucosal secretions result in enhanced translocation of microbial products and whole bacteria across the intestinal mucosal barrier into the systemic circulation.</p

Correlation between the levels of plasma and intestinal IgG and IgA specific for microbial and food antigens, CD4⁺ T cell count, and plasma levels of sCD14.

<p>A) Total and mucosal antigen-specific IgA/IgM ratios in intestinal secretions of individuals not treated with ART (NC and VC) correlate with CD4⁺ T cell count / μl of blood. Correlations with LPS—<i>E</i>. <i>coli</i>, LPS—<i>S</i>. <i>typhi</i>, and yeast mannan antigens showed a similar trend but did not reach statistical significance. B, C) Plasma sCD14 and LPS levels are significantly increased in HIV-1-infected ART-treated and ART-naïve subjects. D) Rectal wash levels of total and mucosal-antigen specific IgA negatively correlate with plasma sCD14 in ART-naïve HIV-1-infected individuals. Correlations were performed using Spearman rank order test; solid lines represent linear regression analysis.</p

Total immunoglobulin levels in plasma and mucosal secretions of HIV-1-infected individuals and uninfected controls.

<p>Total levels of immunoglobulins were determined in plasma, rectal wash, and saliva of uninfected controls (n = 25), HIV-1-infected ART-treated patients with CD4⁺ T cell count > 500 (n = 24), 200–500 (n = 23), and < 200 (n = 16) per μl of blood, ART-untreated individuals not controlling viremia (non-controllers, NC; viral load 3,420–263,000 HIV-1 RNA copies per ml of blood, n = 9) and individuals spontaneously controlling viremia despite the absence of ART (viral controllers, VC; viral load < 1,150 of HIV-1 RNA copies per ml of blood, n = 9). Error bars represent SEM, statistical significance relative to seronegative donors was determined using Mann-Whitney <i>U</i> test (* <i>p</i> < 0.05; ** <i>p</i> < 0.01).</p