IL-15 Complex-Induced IL-10 Enhances Plasmodium-specific CD4+ T Follicular Helper Differentiation and Antibody Production.

Malaria, which results from infection with Plasmodium parasites, remains a major public health problem. Although humans do not develop long-lived, sterilizing immunity, protection against symptomatic disease develops after repeated exposure to Plasmodium parasites and correlates with the acquisition of humoral immunity. Despite the established role Abs play in protection from malaria disease, dysregulated inflammation is thought to contribute to the suboptimal immune response to Plasmodium infection. Plasmodium berghei ANKA (PbA) infection results in a fatal severe malaria disease in mice. We previously demonstrated that treatment of mice with IL-15 complex (IL-15C; IL-15 bound to an IL-15Rα-Fc fusion protein) induces IL-10 expression in NK cells, which protects mice from PbA-induced death. Using a novel MHC class II tetramer to identify PbA-specific CD4+ T cells, in this study we demonstrate that IL-15C treatment enhances T follicular helper (Tfh) differentiation and modulates cytokine production by CD4+ T cells. Moreover, genetic deletion of NK cell-derived IL-10 or IL-10R expression on T cells prevents IL-15C-induced Tfh differentiation. Additionally, IL-15C treatment results in increased anti-PbA IgG Ab levels and improves survival following reinfection. Overall, these data demonstrate that IL-15C treatment, via its induction of IL-10 from NK cells, modulates the dysregulated inflammation during Plasmodium infection to promote Tfh differentiation and Ab generation, correlating with improved survival from reinfection. These findings will facilitate improved control of malaria infection and protection from disease by informing therapeutic strategies and vaccine design.

SARS-CoV-2 shedding and evolution in patients who were immunocompromised during the omicron period: a multicentre, prospective analysis.

BACKGROUND: Prolonged SARS-CoV-2 infections in people who are immunocompromised might predict or source the emergence of highly mutated variants. The types of immunosuppression placing patients at highest risk for prolonged infection have not been systematically investigated. We aimed to assess risk factors for prolonged SARS-CoV-2 infection and associated intrahost evolution. METHODS: In this multicentre, prospective analysis, participants were enrolled at five US medical centres. Eligible patients were aged 18 years or older, were SARS-CoV-2-positive in the previous 14 days, and had a moderately or severely immunocompromising condition or treatment. Nasal specimens were tested by real-time RT-PCR every 2-4 weeks until negative in consecutive specimens. Positive specimens underwent viral culture and whole genome sequencing. A Cox proportional hazards model was used to assess factors associated with duration of infection. FINDINGS: From April 11, 2022, to Oct 1, 2022, 156 patients began the enrolment process, of whom 150 were enrolled and included in the analyses. Participants had B-cell malignancy or anti-B-cell therapy (n=18), solid organ transplantation or haematopoietic stem-cell transplantation (HSCT; n=59), AIDS (n=5), non-B-cell malignancy (n=23), and autoimmune or autoinflammatory conditions (n=45). 38 (25%) participants were real-time RT-PCR-positive and 12 (8%) were culture-positive 21 days or longer after initial SARS-CoV-2 detection or illness onset. Compared with the group with autoimmune or autoinflammatory conditions, patients with B-cell dysfunction (adjusted hazard ratio 0·32 [95% CI 0·15-0·64]), solid organ transplantation or HSCT (0·60 [0·38-0·94]), and AIDS (0·28 [0·08-1·00]) had longer duration of infection, defined as time to last positive real-time RT-PCR test. There was no significant difference in the non-B-cell malignancy group (0·58 [0·31-1·09]). Consensus de novo spike mutations were identified in five individuals who were real-time RT-PCR-positive longer than 56 days; 14 (61%) of 23 were in the receptor-binding domain. Mutations shared by multiple individuals were rare (<5%) in global circulation. INTERPRETATION: In this cohort, prolonged replication-competent omicron SARS-CoV-2 infections were uncommon. Within-host evolutionary rates were similar across patients, but individuals with infections lasting longer than 56 days accumulated spike mutations, which were distinct from those seen globally. Populations at high risk should be targeted for repeated testing and treatment and monitored for the emergence of antiviral resistance. FUNDING: US Centers for Disease Control and Prevention.