Regulatory T Cells Are Locally Induced during Intravaginal Infection of Mice withNeisseria gonorrhoeae

Abstract

Neisseria gonorrhoeae is a gram-negative diplococcus that in human beings produces gonorrhea. Much clinical evidence has led to the conclusion that gonococcus has important mechanisms to evade host immune functions; however, these mechanisms are only now beginning to be elucidated. In this study, we determined that the BALB/c mouse is a good animal model to study gonococcus infection and examined the immune response against the bacteria. We determined that after intravaginal inoculation of mice with Neisseria gonorrhoeae, the bacteria reached and invaded the upper female reproductive tissues and elicited a T-cellspecific immune response associated with a very weak humoral response, altogether resembling gonococcus infection and disease in women. Remarkably, in the draining lymph nodes of the genital tracts of infected mice, we found an increase of regulatory T lymphocytes, namely, transforming growth factor ␤1-positive CD4 ؉ T cells and CD4؉ CD25 ؉ Foxp3 ؉ T cells. Altogether, results indicate that N. gonorrhoeae induces regulatory T cells, which might be related to the local survival of the pathogen and the establishment of a chronic asymptomatic infection.

Chlamydial Infection Increases Gonococcal Colonization in a Novel Murine Coinfection Model

“…N. gonorrhoeae also cannot use murine lactoferrin or transferrin as sources of iron (14,43), and the gonococcal immunoglobulin A1 (IgA1) protease cannot cleave mouse IgA (40). Despite these host restrictions, studying gonococcal pathogenesis in the murine model has yielded considerable insight into the host response to infection (25,31,58,76) and the role of certain gonococcal virulence factors in evasion of host defenses (34,75,81,84,85). The mouse model has also allowed the demonstration of hormonal (13,32,73), as well as the effect of certain antibiotic resistance mutations on microbial fitness (82).…”

Mucosal Immunity and Evasion Strategies of Neisseria gonorrhoeae

“…In regard to the role of regulatory T (Treg) cells, we showed that in Balb/c, the mouse model of gonococcus infections, N. gonorrhoeae induces transforming growth factor 1 (TGF-1)+ CD4 + T cells in the mucosal lymph nodes, including a subset of CD25+Foxp3+ Tregs, indicating that type of response may avoid the host mechanisms of protection (Imarai et al, 2008). Mature CD4+ CD25-T cells can be converted in Treg cells in peripheral tissues under immunosuppressive conditions, such as exposure to IL-10 or TGF-1 made by antigen presenting cells (Sakaguchi, 2004).…”

“…Interestingly, studies in this model revealed several features of infection that mimic a good spectrum of the characteristics of the human disease. Some of them seem highly valuable, (i) the bacteria introduced in the vagina not only invade and colonize the lower genital tract, but also spread to the upper organs (uterus and oviducts) , (ii) infection occurs with no signs of the disease, just as it occurs in a high percentage of women during natural infection (Farley et al, 2003;Inaba et al, 1992) and (iii) the bacteria remains alive within the internal compartments of the infected cells, invading uterine tissues up to 22 days post inoculation (Imarai et al, 2008).…”

“…In Balb/c mice, N. gonorrhoeae is able to reach the upper genital organs and to invade uterine tissue, as it occurs in humans (Imarai et al, 2008;Jerse, 1999). Interestingly, studies in this model revealed several features of infection that mimic a good spectrum of the characteristics of the human disease.…”

“…Increased of neutrophils and macrophage in site of infection (Song et al, 2008) N. gonorrhoeae mice infection IgG>IgA>IgM in vaginal fluid (Song et al, 2008) Whole-protein extractes of N. gonorrhoeae P9-17 Low titers of IgG in serum (Imarai et al, 2008) N. gonorrhoeae Th17 profile immune response and increased IL-17 (Feinen et al, 2010) IgA1 protease Th1 pro-inflammatory profile with increased IFN and TNF (Tsirpouchtsidis et al, 2002) IgA1 protease IL-1 , IL-6, TNF and IL-8 (Lorenzen et al, 1999) Porin Th2 Similarly, in the murine model of infection, no antibody induced response has been detected. In Balb/c mice, N. gonorrhoeae is able to reach the upper genital organs and to invade uterine tissue, as it occurs in humans (Imarai et al, 2008;Jerse, 1999).…”