Clostridioides difficile (C. difficile) is the major cause of hospital-acquired gastrointestinal infections in individuals following antibiotics treatment. The pathogenesis of C. difficile infection (CDI) is mediated mainly by the production of toxins that induce tissue damage and host inflammatory responses. While innate immunity is well characterized in human and animal models of CDI, adaptive immune responses remain poorly understood. In this review, the current understanding of adaptive immunity is summarized and its influence on pathogenesis and disease outcome is discussed. The perspectives on what we believe to be the main pending questions and the focus of future research are also provided. There is no doubt that the innate immune response provides a first line of defense to CDI. But, is the adaptive immune response a friend or a foe? Probably it depends on the course of the disease. Adaptive immunity is essential for pathogen eradication, but may also trigger uncontrolled or pathological inflammation. Most of the understanding of the role of T cells is based on findings from experimental models. While they are a very valuable tool for research studies, more studies in human are needed to translate these findings into human disease. Another main challenge is to unravel the role of the different T cell populations on protection or induction of immunopathogenesis.
Tuberculosis dates back to ancient times but it is not a problem of the past. Each year, millions of people die from tuberculosis. After inhalation of infectious droplet nuclei, Mycobacterium tuberculosis reaches the lungs where it can manipulate the immune system and survive within host macrophages, establishing a persistent infection. The signaling lymphocytic activation molecule family member 1 (SLAMF1) is a self-ligand receptor that can internalize gram-negative bacteria and regulate macrophages' phagosomal functions. In tuberculosis, SLAMF1 promotes Th1-protective responses. In this work, we studied the role of SLAMF1 on macrophages' functions during M. tuberculosis infection. Our results showed that both M. tuberculosis and IFNstimulation induce SLAMF1 expression in macrophages from healthy donor and Tohoku Hospital Pediatrcs-1 cells. Costimulation through SLAMF1 with an agonistic antibody resulted in an enhanced internalization of M. tuberculosis by macrophages. Interestingly, we found that SLAMF1 interacts with M. tuberculosis and colocalizes with the bacteria and with early and late endosomes/lysosomes markers (EEA1 and LAMP2), suggesting that SLAMF1 recognize M. tuberculosis and participate in the endolysosomal maturation process. Notably, increased levels of SLAMF1 were detected in CD14 cells from pleural effusions of tuberculosis patients, indicating that SLAMF1 might have an active function at the site of infection. Taken together, our results provide evidence that SLAMF1 improves the uptake of M. tuberculosis by human monocyte-derived macrophages.
IntroductionTuberculosis (TB) is now the 2nd leading infectious killer after COVID-19 and the 13th leading cause of death worldwide. Moreover, TB is a lethal combination for HIV-patients. Th1 responses and particularly IFN-γ are crucial for immune protection against Mycobacterium tuberculosis infection. Many gene variants for IFNG that confer susceptibility to TB have been described in multiple ethnic populations. Likewise, some epigenetic modifications have been evaluated, being CpG methylation the major epigenetic mark that makes chromatin inaccessible to transcription factors, thus avoiding the initiation of IFNG transcription.MethodsWe evaluated both genetic and epigenetic changes involved in IFN-γ production and TB susceptibility in Argentine population. Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was performed for the IFN-γ +874 A/T polymorphism (rs2430561) genotyping in 199 healthy donors (HD) and 173 tuberculosis (TB) patients. IFN-γ levels from M. tuberculosis-stimulated PBMCs were measured by ELISA. The methylation status at the -53 CpG site of the IFNG promoter in individuals with latent infection (LTBI), TB and HD was determine by pyrosequencing.ResultsUsing a case-control study, we found that A allele and, consequently, AA genotype were overrepresented in patients with active disease. Moreover, HD carrying T allele (AT or TT genotype) evidenced an augmented IFN-γ secretion compared to TB patients. Codominance was the genetic model that best fits our results according to the Akaike information criterion (AIC). In addition, increased methylation levels at the -53 CpG site in the IFN-γ promoter were observed in whole blood of patients with active TB compared to LTBI individuals.DiscussionIFN-γ is regulated by genetic variants and epigenetic modifications during TB. Besides, AA genotype of the rs2430561 single nucleotide polymorphism could be considered as a potential TB susceptibility genetic biomarker in Argentina and the methylation of the -53 CpG site could result in a useful predictor of TB reactivation.
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