RESUMO
Frequent recrudescence is responsible for persistent Plasmodium infection after the acute stage. Our previous study demonstrated that phagocytic cells are essential for controlling Plasmodium chabaudi chabaudi AS (P. chabaudi) recrudescence. Nevertheless, the specific type of phagocytic cells involved in controlling P. chabaudi recrudescence, as well as their underlying molecular mechanisms of action, remain elusive. Herein we employ single-cell RNA sequencing (scRNA-seq) to analyse splenic phagocytic cells during both the acute and recrudescent phases of P. chabaudi infection. Using scRNA-seq, we found that monocyte-derived macrophages (MDMs) declined during the acute stage of P. chabaudi blood-stage infection, and then expanded rapidly in the recrudescence stage. The changing trend of MDMs was confirmed by flow cytometry. To explore the potential role of MDMs in controlling parasitemic recrudescence, MDMs were reduced by a low dose of clodronate liposomes (CLs) during the recrudescence stage, which significantly elevated the P. chabaudi parasitemia. Additionally, no significant difference in the proportion of splenic MDMs or classical monocytes (CMs) within the monocyte population was observed between the infected CCR2-/- mice and their control littermates, suggesting that the transition from CMs to MDMs may not occur in this model. The results indicate that MDMs potentially play a protective role in preventing malarial parasitemic recrudescence, offering valuable insights into immune-based interventions against Plasmodium infection and potentially contributing to the prevention of malaria transmission.
Assuntos
Macrófagos , Malária , Infecção Persistente , Plasmodium chabaudi , Animais , Camundongos , Plasmodium chabaudi/imunologia , Modelos Animais de Doenças , Macrófagos/imunologia , Malária/imunologia , Malária/parasitologia , Malária/prevenção & controle , Camundongos Endogâmicos C57BL , Feminino , Parasitemia/imunologia , Parasitemia/parasitologia , Parasitemia/prevenção & controle , Monócitos/imunologia , Baço/imunologia , Ácido Clodrônico/administração & dosagem , Análise de Célula Única , Infecção Persistente/imunologia , Infecção Persistente/prevenção & controleRESUMO
BACKGROUND: Male circumcision reduces the risk of human immunodeficiency virus infection in men. We assessed the effect of male circumcision on the incidence and natural history of human papillomavirus (HPV) in a randomized clinical trial in Kisumu, Kenya. METHODS: Sexually active, 18- to 24-year-old men provided penile exfoliated cells for HPV DNA testing every 6 months for 2 years. HPV DNA was detected via GP5+/6+ PCR in glans/coronal sulcus and in shaft samples. HPV incidence and persistence were assessed by intent-to-treat analyses. RESULTS: A total of 2,193 men participated (1,096 randomized to circumcision; 1,097 controls). HPV prevalence was 50% at baseline for both groups and dropped to 23.7% at 24 months in the circumcision group, and 41.0% in control group. Incident infection of any HPV type over 24 months was lower among men in the circumcision group than in the control group [HR = 0.61; 95% confidence interval (CI), 0.52-0.72]. Clearance rate of any HPV infection over 24 months was higher in the circumcision group than in the control group (HR = 1.87; 95% CI, 1.49-2.34). Lower HPV point-prevalence, lower HPV incidence, and higher HPV clearance in the circumcision group were observed in glans but not in shaft samples. CONCLUSION: Male circumcision reduced the risk of HPV acquisition and reinfection, and increased HPV clearance in the glans. IMPACT: Providing voluntary, safe, and affordable male circumcision should help reduce HPV infections in men, and consequently, HPV-associated disease in their partners.
Assuntos
Circuncisão Masculina/estatística & dados numéricos , Infecções por Papillomavirus/epidemiologia , Doenças do Pênis/epidemiologia , Pênis/virologia , Infecção Persistente/epidemiologia , Adolescente , Alphapapillomavirus/genética , Alphapapillomavirus/isolamento & purificação , DNA Viral/isolamento & purificação , Humanos , Incidência , Análise de Intenção de Tratamento , Quênia , Masculino , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Doenças do Pênis/diagnóstico , Doenças do Pênis/prevenção & controle , Doenças do Pênis/virologia , Pênis/cirurgia , Infecção Persistente/diagnóstico , Infecção Persistente/prevenção & controle , Infecção Persistente/virologia , Resultado do Tratamento , Adulto JovemRESUMO
Chronic infection of hepatitis B virus (HBV) is a high risk factor for hepatic diseases, such as liver fibrosis, cirrhosis and hepatocellular carcinoma. Non-responders and hyporesponders to HBV vaccine are not protected from HBV infection. Patients that achieve autonomous or treatment-induced recovery are at risk of reactivation due to persistence of HBV covalently closed circular DNA (cccDNA) in hepatocytes. Interleukin 21 (IL-21) is a key regulator of HBV clearance in mouse models of HBV persistence: IL-21-based therapies effectively induces HBV clearance and protects mice from subsequent re-challenge. In this study, we explore the possibility of using IL-21 as prophylaxis against HBV by using mouse models of HBV persistence. HBV-naïve mice were transiently exposed to exogenous IL-21 through injection with recombinant adeno-associated virus expressing mouse IL-21 (AAV-IL-21). After extraneous IL-21 protein and DNA had become undetectable, mice were challenged with persistence-inducing HBV replicon plasmid through hydrodynamic injection. Viral persistence was analyzed by measuring viral antigens and DNA markers in serum and intrahepatic HBV DNA. For mechanistic studies, CD8+ T cell functions were blocked by repeated intraperitoneal injections of CD8 monoclonal antibodies in HBV-challenged mice. AAV-IL-21-injected mice quickly cleared HBV after HBV replicon challenge. In contrast, untreated mice and mice injected with control virus (AAV-Ctrl) allowed establishment of HBV persistence. Mechanistically, mice with prior IL-21 exposure displayed marked intrahepatic CD8+ T cell infiltrations, and CD8 blocking experiments demonstrated that CD8+ T cell responses functionally contributed toward clearance.