Abstract
Neisseria gonorrhoeae is the second most common sexually transmitted bacterial pathogen worldwide. Diseases associated with N. gonorrhoeae cause localized inflammation of the urethra and cervix. Despite this inflammatory response, infected individuals do not develop protective adaptive immune responses to N. gonorrhoeae. N. gonorrhoeae is a highly adapted pathogen that has acquired multiple mechanisms to evade its host's immune system, including the ability to manipulate multiple immune signaling pathways. N. gonorrhoeae has previously been shown to engage immunosuppressive signaling pathways in B and T lymphocytes. We have now found that N. gonorrhoeae also suppresses adaptive immune responses through effects on antigen presenting cells. Using primary, murine bone marrow-derived dendritic cells and lymphocytes, we show that N. gonorrhoeae-exposed dendritic cells fail to elicit antigen-induced CD4+ T lymphocyte proliferation. N. gonorrhoeae exposure leads to upregulation of a number of secreted and dendritic cell surface proteins with immunosuppressive properties, particularly Interleukin 10 (IL-10) and Programmed Death Ligand 1 (PD-L1). We also show that N. gonorrhoeae is able to inhibit dendritic cell- induced proliferation of human T-cells and that human dendritic cells upregulate similar immunosuppressive molecules. Our data suggest that, in addition to being able to directly influence host lymphocytes, N. gonorrhoeae also suppresses development of adaptive immune responses through interactions with host antigen presenting cells. These findings suggest that gonococcal factors involved in host immune suppression may be useful targets in developing vaccines that induce protective adaptive immune responses to this pathogen.
Highlights
There are approximately 60 million cases of N. gonorrhoeae infection each year worldwide [1]
In dendritic cells exposed to a higher inoculum, more than 99% of intracellular N. gonorrhoeae were eliminated by 1 hour, and no intracellular N. gonorrhoeae were detectable at 24 hours, even when extracellular gentamicin was removed from the culture (Figure S1)
After 24 hours of exposure to ovalbumin or ovalbumin with N. gonorrhoeae, dendritic cells were washed to remove excess bacteria and bacterial products, and these cells were co-cultured with carboxyfluorescein succinimidyl ester (CFSE)-labeled, enriched T lymphocytes from OT-II mice
Summary
There are approximately 60 million cases of N. gonorrhoeae infection each year worldwide [1]. N. gonorrhoeae generally infects the female cervix or male urethra, where the local inflammatory response to mucosal invasion by the organism leads to symptoms of urethritis or cervicitis. Asymptomatic infection or colonization of mucosal surfaces with minimal inflammatory response occurs in approximately half of all infected individuals [2,3]. N. gonorrhoeae infections significantly impact female reproductive health, as ascending infections of fallopian tubes are associated with infertility and perinatal infection can be transmitted to the neonate during birth. Infection with N. gonorrhoeae is associated with increased risk of HIV transmission through effects on both HIV-infected and HIV-uninfected individuals. HIV-uninfected individuals with gonorrhea have increased numbers of inflammatory cells in their genital mucosa, some of which are susceptible to HIV infection, thereby increasing the risk that N. gonorrhoeae-infected individuals will acquire HIV from HIV-infected partners. Prevention of N. gonorrhoeae infection is an important public health issue
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