Vibrio cholerae Porin OmpU Induces Pro-Inflammatory Responses, but Down-Regulates LPS-Mediated Effects in RAW 264.7, THP-1 and Human PBMCs

Abstract

Vibrio cholerae porin OmpU plays a crucial role in the survival of the organism in the human gut. Various observations suggest critical involvement of OmpU in V. cholerae pathogenesis. However, OmpU is poorly characterized in terms of its ability to evoke cellular responses, particularly in the context of host immune system. Therefore, towards characterizing V. cholerae OmpU for its host immunomodulatory functions, we have studied the ability of OmpU to elicit pro-inflammatory responses in a range of immune cells which include, mouse RAW 264.7 macrophages, human THP-1 monocytes and human PBMCs. We have observed that purified OmpU induces pro-inflammatory responses in terms of production of NO, TNFα and IL-6. Interestingly, pre-treatment of the cells with OmpU suppresses the production of NO, TNFα, IL-6 as well as IL-12 upon subsequent activation with LPS. Our results therefore suggest that V. cholerae OmpU may have a differential regulatory role in terms of host immunomodulatory function: it can induce pro-inflammatory responses in target host immune cells, whereas it can also exert suppressive effect on LPS-induced pro-inflammatory responses. In addition, our study indicates that purified OmpU may have the ability to skew the Th1 response towards the Th2 response, presumably via suppression of IL-12 production.

Immuno-Modulatory Role of Porins: Host Immune Responses, Signaling Mechanisms and Vaccine Potential

“…induce pro-infl ammatory cytokines like TNFα, IL-6 and IL-1β secretion in a variety of cell lines and primary cells, such as monocytes and macrophages of human and mouse origin (Table 6.1 ) (Tufano et al 1994(Tufano et al , 1995Toussi et al 2012 ;Galdiero et al 2001aGaldiero et al , b , 2004Vitiello et al 2004Vitiello et al , 2011Liu et al 2010 ;Singleton et al 2005 ;Massari et al 2006 ;Al-Bader et al 2004 ;Moreno-Eutimio et al 2013, Galdiero et al 2005, 2006aRay et al 2003 ;Biswas et al 2007 ;Elena et al 2009 ;Pore et al 2012 ). Vibrio cholerae OmpU stimulates monocytes and macrophages to produce TNFα and IL-6 (Sakharwade et al 2013 ). Omp16 of Brucella abortus , an outer membrane protein lipid anchor induces TNFα and IL-12 in mouse derived macrophages (Pasquevich et al 2010 ).…”

“…PorA of Neisseria meningitidis induces IL-12 secretion in human PBMCs (peripheral blood mononuclear cells) derived DCs (Al-Bader et al 2004 ). Salmonella porins, OmpA of Shigella fl exineri and OmpU of V. cholerae are able to stimulate nitric oxide production in macrophages of mouse origin (Sakharwade et al 2013 ;Pore et al 2012 ;Gupta et al 1999 ). In contrast to the reports demonstrating porin-induced pro-infl ammatory responses, Salmonella porins which are pro-infl ammatory in nature can also induce the production of IL-10, a potent immune-suppressive cytokine in human cell line and mouse primary cells (Galdiero et al 2005 ).…”

Vibrio cholerae porin OmpU mediates M1-polarization of macrophages/monocytes via TLR1/TLR2 activation

“…It has been shown in various studies, that porins are involved in the bacterial adherence processes and in the induction of apoptosis of the host cells (Bernardini et al, 1993;Muller et al, 1999;Negm and Pistole, 1999). Roles of porins in inducing pro-inflammatory responses, and their underlying signaling processes have been established in various reports (Biancone et al, 1997;Biswas, 2000;Galdiero et al, 2001;Gupta et al, 1999;Sakharwade et al, 2013;Sakharwade et al, 2015). Due to its immuno-modulatory property, porins are thought to be the potential vaccine candidate (Latz et al, 2004;Tabaraie et al, 1994).…”

Vibrio cholerae Porin OmpU Induces Caspase-independent Programmed Cell Death upon Translocation to the Host Cell Mitochondria

“…It probably acts as an adhesin as well, although there are contrasting reports regarding its role in adhesion (35)(36)(37). Moreover, OmpU has been shown to possess the ability to down-regulate the LPS-mediated pro-inflammatory effect (28). Therefore, its regulation and reported functions imply that OmpU may have a major role in the bacterial pathogenesis process.…”