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Abstract
Despite its importance in modulating HSV-2 pathogenesis, the nature of tissue-resident immune memory to HSV-2 is not completely understood. We used genital HSV-2 infection of guinea pigs to assess the type and location of HSV-specific memory cells at peripheral sites of HSV-2 infection. HSV-specific antibody-secreting cells were readily detected in the spleen, bone marrow, vagina/cervix, lumbosacral sensory ganglia, and spinal cord of previously-infected animals. Memory B cells were detected primarily in the spleen and to a lesser extent in bone marrow but not in the genital tract or neural tissues suggesting that the HSV-specific antibody-secreting cells present at peripheral sites of HSV-2 infection represented persisting populations of plasma cells. The antibody produced by these cells isolated from neural tissues of infected animals was functionally relevant and included antibodies specific for HSV-2 glycoproteins and HSV-2 neutralizing antibodies. A vigorous IFN-γ-secreting T cell response developed in the spleen as well as the sites of HSV-2 infection in the genital tract, lumbosacral ganglia and spinal cord following acute HSV-2 infection. Additionally, populations of HSV-specific tissue-resident memory T cells were maintained at these sites and were readily detected up to 150 days post HSV-2 infection. Unlike the persisting plasma cells, HSV-specific memory T cells were also detected in uterine tissue and cervicothoracic region of the spinal cord and at low levels in the cervicothoracic ganglia. Both HSV-specific CD4+ and CD8+ resident memory cell subsets were maintained long-term in the genital tract and sensory ganglia/spinal cord following HSV-2 infection. Together these data demonstrate the long-term maintenance of both humoral and cellular arms of the adaptive immune response at the sites of HSV-2 latency and virus shedding and highlight the utility of the guinea pig infection model to investigate tissue-resident memory in the setting of HSV-2 latency and spontaneous reactivation.
Highlights
HSV-2 infection is widespread globally with an estimated 23.6 million new infections occurring each year [1]
We hypothesized that these antibody secreting cells (ASCs) represented long-lived plasma cells existing in survival niches at these sites of chronic inflammation an alternative explanation is that these ASC derived from tissue-resident memory B cells as a result of periodic exposure to HSV antigens released during reactivation events
These results suggest that the vast majority of HSV-specific ASC present in the lower genital tract, lumbosacral ganglia and adjacent spinal cord on days 49-70 post infection represented a persisting population of plasma cells
Summary
HSV-2 infection is widespread globally with an estimated 23.6 million new infections occurring each year [1]. Similar populations of tissue-resident HSV-specific CD4+ and CD8+ T cells have been found in latently infected trigeminal ganglia of humans [16, 17, 18] and in mice following ocular HSV-1 infection [19, 20]. Infection of mice with fully virulent HSV-2 commonly results in encephalitis and death, precluding easy analysis of the magnitude, phenotype and function of virus specific ganglia- and spinal cord-resident memory T cells in this animal model. Virus is transported by retrograde transport to cell bodies in the sensory ganglia and autonomic neurons in spinal cords [10] During this phase of infection, the virus establishes a latent infection and, similar to humans, the animals undergo spontaneous, intermittent reactivation of virus. HSV-2 recurrences may manifest as clinically apparent disease with erythematous and/or vesicular lesions on the perineum or as asymptomatic recurrences characterized by shedding of virus from the genital tract
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