Considerable concerns relating to the duration of protective immunity against SARS-CoV-2 exist, with evidence of antibody titres declining rapidly after infection and reports of reinfection. Here we monitor the antibody responses against SARS-CoV-2 receptor binding domain (RBD) for up to six months after infection. While antibody titres are maintained, about 13% of the cohort’s neutralising responses return to background. However, encouragingly in a selected subset of 13 participants, 12 have detectable RBD-specific memory B cells and these generally are increasing out to 6 months. Furthermore, we are able to generate monoclonal antibodies with SARS-CoV-2 neutralising capacity from these memory B cells. Overall our study suggests that the loss of neutralising antibodies in plasma may be countered by the maintenance of neutralising capacity in the memory B cell repertoire.

Interleukin-23 (IL-23The resurgence of Mycobacterium tuberculosis infection linked to the human immunodeficiency virus epidemic highlights the importance of cellular immunity in controlling the growth of this pathogen. Effective host defense against pulmonary infection with M. tuberculosis requires the coordinated actions of both the innate and adaptive immune systems (10). Interleukin-12 (IL-12) is well-established as a cytokine released by antigen-presenting cells early in M. tuberculosis infection, and this cytokine is critical for the generation of a Th1 polarized adaptive immune response and subsequent host defenses. Indeed, the exogenous administration of IL-12 augments M. tuberculosis clearance (6,11,25). IL-23 has recently been identified as a member of the IL-12 cytokine family and may also play a role in host defense against this pathogen. IL-23 is a heterodimer that shares an identical p40 subunit with IL-12 but contains a unique p19 chain that closely resembles IL-12 p35 (26). Secreted by dendritic cells and other antigenpresenting cells, IL-23 stimulates the production of gamma interferon (IFN-␥) by activated/memory CD45RO ϩ T cells but not naïve CD45RA ϩ cells. In contrast, IL-12 elicits IFN-␥ from both subsets. IL-23 also induces the proliferation of activated/ memory T cells but not naïve T cells. IL-12 and IL-23 share binding affinity for the IL-12R␤1 subunit; however, IL-23 binds to a distinct IL-23 receptor (IL-23R), whereas IL-12 utilizes IL-12R␤2 as its coreceptor (27).The comparative roles of IL-12 and IL-23 in host defense against a variety of infections are actively under investigation. Through Toll-like receptor 4 signaling, IL-23, but not IL-12, has been shown to play a critical role in stimulating T-cell release of IL-17 following infection with Klebsiella pneumoniae (15), while specific roles for IL-23 in immune defense against the intracellular bacteria Salmonella enteritidis and Francisella tularensis have also been found (9, 21). In regard to M. tuberculosis infections, recent studies have demonstrated a greater sensitivity in IL-12/23 p40 Ϫ/Ϫ mice than in IL-12 p35 Ϫ/Ϫ animals (5, 17). Moreover, macrophages rapidly express IL-23 when exposed to mycobacterial antigens, suggesting an immune-stimulatory role for this cytokine during infection (4, 33).The evidence of a role for IL-23 in the development of immunity against several intracellular pathogens, together with increasing interest in the use of biologic response modifiers to treat disease, led us to study the effects of localized, transient expression of IL-23 during early pulmonary M. tuberculosis infection. In this report, we show that local IL-23 gene delivery using a replication-defective adenovirus vector (AdIL-23) resulted in markedly decreased mycobacterial burden in the lungs up to 28 days after infection. AdIL-23 treatment significantly decreased lung inflammation in infected animals despite increasing numbers of activated CD4 ϩ T cells in lungs and draining lymph nodes. Cultures of T cells from draining

Understanding the long-term maintenance of SARS-CoV-2 immunity is critical for predicting protection against reinfection. In an age and gender matched cohort of 24 participants, the association of disease severity and early immune responses on the maintenance of humoral immunity 12 months post-infection is examined. All severely affected participants maintain a stable subset of SARS-CoV-2 receptor-binding domain (RBD)-specific memory B cells (MBCs) and good neutralising antibody breadth against the majority of the variants of concern, including the Delta variant. Modelling these immune responses against vaccine efficacy data indicate 45-76% protection against symptomatic infection (variant dependent). Overall, these findings indicate durable humoral responses in most participants after infection, reasonable protection against reinfection, and implicate baseline antigen-specific CD4+ T cell responses as a predictor of maintenance of antibody neutralisation breadth and RBD-specific MBC levels at 12 months post-infection.

Prior HSV-2 infection enhances the acquisition of HIV-1 >3-fold. In genital herpes lesions, the superficial layers of stratified squamous epithelium are disrupted, allowing easier access of HIV-1 to Langerhans cells (LC) in the epidermis and perhaps even dendritic cells (DCs) in the outer dermis, as well as to lesion infiltrating activated T lymphocytes and macrophages. Therefore, we examined the effects of coinfection with HIV-1 and HSV-2 on monocyte-derived DCs (MDDC). With simultaneous coinfection, HSV-2 significantly stimulated HIV-1 DNA production 5-fold compared with HIV-1 infection alone. Because <1% of cells were dually infected, this was a field effect. Virus-stripped supernatants from HSV-2–infected MDDCs were shown to enhance HIV-1 infection, as measured by HIV-1–DNA and p24 Ag in MDDCs. Furthermore these supernatants markedly stimulated CCR5 expression on both MDDCs and LCs. TNF-α was by far the most prominent cytokine in the supernatant and also within HSV-2–infected MDDCs. HSV-2 infection of isolated immature epidermal LCs, but not keratinocytes, also produced TNF-α (and low levels of IFN-β). Neutralizing Ab to TNF-α and its receptor, TNF-R1, on MDDCs markedly inhibited the CCR5-stimulating effect of the supernatant. Therefore, these results suggest that HSV-2 infection of DCs in the skin during primary or recurrent genital herpes may enhance HIV-1 infection of adjacent DCs, thus contributing to acquisition of HIV-1 through herpetic lesions.

Peripheral immunity plays a key role in maintaining homeostasis and conferring crucial neuroprotective effects on the injured nervous system, while at the same time may contribute to increased vulnerability to neuropathic pain. Little is known about the reciprocal relationship between entrapment neuropathy and peripheral immunity. This study investigated immune profile in patients with carpal tunnel syndrome (CTS), the most prevalent entrapment neuropathy. All patients exhibited neurophysiological abnormalities in the median nerve, with the majority reporting neuropathic pain symptoms. We found a significant increase in serum CCL5, CXCL8, CXCL10 and VEGF, and in CD4+ central and effector memory T cells in CTS patients, as compared to healthy controls. CCL5 and VEGF were identified as having the highest power to discriminate between patients and controls. Interestingly, and contrary to the prevailing view of CCL5 as a pro-nociceptive factor, the level of circulating CCL5 was inversely correlated with neuropathic pain intensity and median nerve motor latency. In contrast, the level of central memory T cells was positively associated with abnormal neurophysiological findings. These results suggest that entrapment neuropathy is associated with adaptive changes in the homeostasis of memory T cells and an increase in systemic inflammatory modulating cytokines/chemokines, which potentially regulate neuropathic symptoms.

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