Manganese uptake by MtsABC contributes to the pathogenesis of human pathogen group A streptococcus by resisting host nutritional immune defenses.

The interplay between host nutritional immune mechanisms and bacterial nutrient uptake systems has a major impact on the disease outcome. The host immune factor calprotectin (CP) limits the availability of essential transition metals, such as manganese (Mn) and zinc (Zn), to control the growth of invading pathogens. We previously demonstrated that the competition between CP and the human pathogen group A streptococcus (GAS) for Zn impacts GAS pathogenesis. However, the contribution of Mn sequestration by CP in GAS infection control and the role of GAS Mn acquisition systems in overcoming host-imposed Mn limitation remain unknown. Using a combination of in vitro and in vivo studies, we show that GAS-encoded mtsABC is a Mn uptake system that aids bacterial evasion of CP-imposed Mn scarcity and promotes GAS virulence. Mn deficiency caused by either the inactivation of mtsC or CP also impaired the protective function of GAS-encoded Mn-dependent superoxide dismutase. Our ex vivo studies using human saliva show that saliva is a Mn-scant body fluid, and Mn acquisition by MtsABC is critical for GAS survival in human saliva. Finally, animal infection studies using wild-type (WT) and CP-/- mice showed that MtsABC is critical for GAS virulence in WT mice but dispensable in mice lacking CP, indicating the direct interplay between MtsABC and CP in vivo. Together, our studies elucidate the role of the Mn import system in GAS evasion of host-imposed metal sequestration and underscore the translational potential of MtsABC as a therapeutic or prophylactic target.

AMPs as Host-Directed Immunomodulatory Agents against Skin Infections Caused by Opportunistic Bacterial Pathogens.

Skin is the primary and largest protective organ of the human body. It produces a number of highly evolved arsenal of factors to counter the continuous assault of foreign materials and pathogens from the environment. One such potent factor is the repertoire of Antimicrobial Peptides (AMPs) that not only directly destroys invading pathogens, but also optimally modulate the immune functions of the body to counter the establishment and spread of infections. The canonical direct antimicrobial functions of these AMPs have been in focus for a long time to design principles for enhanced therapeutics, especially against the multi-drug resistant pathogens. However, in recent times the immunomodulatory functions performed by these peptides at sub-microbicidal concentrations have been a point of major focus in the field of host-directed therapeutics. Such strategies have the added benefit of not having the pathogens develop resistance against the immunomodulatory pathways, since the pathogens exploit these signaling pathways to obtain and survive within the host. Thus, this review summarizes the potent immunomodulatory effect of these AMPs on, specifically, the different host immune cells with the view of providing a platform of information that might help in designing studies to exploit and formulate effective host-directed adjunct therapeutic strategies that would synergies with drug regimens to counter the current diversity of drug-resistant skin opportunistic pathogens.

Attenuation of quorum sensing system and virulence in Vibrio cholerae by phytomolecules.

The Vibrio cholerae, a gram-negative bacterium, is the causative agent of cholera. Quorum sensing is a cell-to-cell communication that leads to gene expression, accumulation of signaling molecules, biofilm formation, and production of virulence factors. The quorum sensing pathway in V. cholerae is regulated by luxO, and biofilm formation and other virulence factors are positively controlled by aphA and negatively by hapR. Hence, targeting the global regulator luxO would be a promising approach to modulate the QS to curtail V. cholerae pathogenesis. The present study investigated the modulating activity of quercetin and naringenin on biofilm formation and quorum-sensing regulated phenotypes in V. cholerae. Then after we determined the anti-quorum sensing capability of phytomolecules against the model organism Chromobacterium violaceum. Also, we performed flow cytometry for live/dead bacteria, MTT assay, CLSM, and growth curve analysis to determine their role as QS modulators rather than anti-bacterial. V. cholerae strains VC287 and N16961 formed thick biofilm. We observed a two-fold reduction in the expression of biofilm-associated genes comprising gbpA, vpsA, rbmA, and mbaA in the presence of phytomolecules indicating that phytomolecules modulate quorum sensing pathway rather than killing the bacteria. These phytomolecules were non-toxic and non-hemolytic and had anti-adhesion and anti-invasion properties. In addition, quercetin and naringenin were found to be highly effective compared to known quorum-sensing inhibitors terrein and furanone C-30. Thus, this study provides evidence that phytomolecules: quercetin and naringenin modulate the quorum-sensing pathway rather than killing the bacteria and can be used as an anti-quorum-sensing molecule for therapy against the pathogen.