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Sexually transmitted infections (STIs) have long been an underestimated opponent in the public health battle. It is estimated that there are 20 million new STI cases in the United States each year, and half of these are among young people aged 15–24 years. Across the nation, at any given time, there are more than 110 million total infections. These infections can lead to long-term health consequences such as infertility and can facilitate HIV transmission. In this chapter, we discuss the immune responses associated with four major bacterial STD pathogens: Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum, and Mycoplasma genitalium. We also discuss the status and challenges of vaccine development for each pathogen.

Sexually transmitted infections with Chlamydia trachomatis and/or Neisseria gonorrhoeae and rates of pelvic inflammatory disease (PID) in women continue to rise, with reinfection being common because of poor adaptive immunity. Diagnosis remains imprecise, and pathogenesis data are derived primarily from monoinfection of mice with C. trachomatis or N. gonorrhoeae. By comparing blood mRNA responses of women with C. trachomatis– and/or N. gonorrhoeae–induced PID and histologic endometritis with those from women with C. trachomatis and/or N. gonorrhoeae infection limited to their cervix and asymptomatic uninfected women determined via microarray, we discovered important pathogenic mechanisms in PID and response differences that provide a pathway to biomarker discovery. Women with N. gonorrhoeae– and/or C. trachomatis–induced PID exhibit overexpression of myeloid cell genes and suppression of protein synthesis, mitochondrial oxidative phosphorylation, and T cell–specific genes. Coinfected women exhibited the greatest activation of cell death pathways and suppression of responses essential for adaptive immunity. Women solely infected with C. trachomatis expressed elevated levels of type I and type II IFN genes, and enhanced type I IFN–induced chemokines in cervical secretions were associated with ascension of C. trachomatis to the endometrium. Blood microarrays reveal discrete pathobiological endotypes in women with PID that are driven by pathogen invasion of the upper genital tract.

Untreated HIV infection is characterized by generalized immune activation, T cell dysfunction, and ultimately the exhaustion of HIV-specific CD8 T cell responses. Durable virus suppression resulting from anti-retroviral therapy (ART) is associated with greatly improved immune function, but some phenotypic and functional abnormalities persist even after years of suppressive ART. We have observed that, relative to HIV-seronegative individuals, CD8 T cells from HIV+ participants on ART are skewed toward a more effector-like (T-bethigh Eomeslow) phenotype and have significantly reduced proliferative capacity in response to antigenic stimulation. Metabolic pathways play a key role in shaping T cell maturation, phenotype, and function, and the ability to produce ATP via both glycolytic and oxidative phosphorylation (mitochondrial) pathways is critical to T cell function and longevity. However, whether underlying metabolic abnormalities contribute to residual CD8 T cell dysfunction in HIV+ individuals on ART has not been fully explored. Here we compare the metabolic phenotype of T cells from HIV+ participants on ART with those from HIV-seronegative participants. We are using MitoTracker® dyes to assess mitochondrial mass and polarization in T cell memory subsets, ex vivo and in response to antigen, and measuring expression of the glucose transporter GLUT1 and the mitochondrial biogenesis master regulator PGC-1α in different CD8 T cell effector subsets. Our findings will inform whether phenotypic and functional abnormalities in CD8 T cells from HIV+ individuals on ART reflect underlying metabolic dysfunction and if metabolic interventions could improve T cell function.