ATG5-regulated CCL2/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4+ Th1 responses.

Parasite-specific CD4+ Th1 cell responses are the predominant immune effector for controlling malaria infection; however, the underlying regulatory mechanisms remain largely unknown. This study demonstrated that ATG5 deficiency in myeloid cells can significantly inhibit the growth of rodent blood-stage malarial parasites by selectively enhancing parasite-specific CD4+ Th1 cell responses. This effect was independent of ATG5-mediated canonical and non-canonical autophagy. Mechanistically, ATG5 deficiency suppressed FAS-mediated apoptosis of LY6G- ITGAM/CD11b+ ADGRE1/F4/80- cells and subsequently increased CCL2/MCP-1 production in parasite-infected mice. LY6G- ITGAM+ ADGRE1- cell-derived CCL2 selectively interacted with CCR2 on CD4+ Th1 cells for their optimized responses through the JAK2-STAT4 pathway. The administration of recombinant CCL2 significantly promoted parasite-specific CD4+ Th1 responses and suppressed malaria infection. Conclusively, our study highlights the previously unrecognized role of ATG5 in modulating myeloid cells apoptosis and sequentially affecting CCL2 production, which selectively promotes CD4+ Th1 cell responses. Our findings provide new insights into the development of immune interventions and effective anti-malarial vaccines.Abbreviations: ATG5: autophagy related 5; CBA: cytometric bead array; CCL2/MCP-1: C-C motif chemokine ligand 2; IgG: immunoglobulin G; IL6: interleukin 6; IL10: interleukin 10; IL12: interleukin 12; MFI: mean fluorescence intensity; JAK2: Janus kinase 2; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; pRBCs: parasitized red blood cells; RUBCN: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; STAT4: signal transducer and activator of transcription 4; Th1: T helper 1 cell; Tfh: follicular helper cell; ULK1: unc-51 like kinase 1.

Malaria oocysts require circumsporozoite protein to evade mosquito immunity.

Malaria parasites are less vulnerable to mosquito immune responses once ookinetes transform into oocysts, facilitating parasite development in the mosquito. However, the underlying mechanisms of oocyst resistance to mosquito defenses remain unclear. Here, we show that circumsporozoite protein (CSP) is required for rodent malaria oocysts to avoid mosquito defenses. Mosquito infection with CSPmut parasites (mutation in the CSP pexel I/II domains) induces nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 5 (NOX5)-mediated hemocyte nitration, thus activating Toll pathway and melanization of mature oocysts, upregulating hemocyte TEP1 expression, and causing defects in the release of sporozoites from oocysts. The pre-infection of mosquitoes with the CSPmut parasites reduces the burden of infection when re-challenged with CSPwt parasites by inducing hemocyte nitration. Thus, we demonstrate why oocysts are invisible to mosquito immunity and reveal an unknown role of CSP in the immune evasion of oocysts, indicating it as a potential target to block malaria transmission.

The Dynamic Change of Immune Responses Between Acute and Recurrence Stages of Rodent Malaria Infection.

Malaria infections are persistent as frequent recrudescence of the disease may occur following the acute infection stage, but the different immune responses that control the acute and recrudescence stages are still largely unknown. Using single-cell RNA sequencing (scRNA-seq), we showed that the number of Th1 and plasma cells in the spleen was significantly reduced during the recurrence stage compared to the acute stage of Plasmodium chabaudi chabaudi AS (P. chabaudi) infection. Additionally, the ability of both CD4+ T cell responses and B cells to control P. chabaudi recurrence was significantly reduced compared to their roles in the control of acute infection. In contrast, the number of innate immune cells, including red pulp macrophages (RPMs), gamma delta (γδ) T cells, and Dendritic cells (DCs) were significantly increased during the recurrence stage and showed to be critical for P. chabaudi infection recurrence control. Thus, our data strongly suggest the complementary role of innate immune responses in controlling malaria recrudescence when adaptive immune responses are suppressed. These findings shed new light on the development of immune interventions against malaria.

Preeclampsia and maternal risk of breast cancer: a meta-analysis of cohort studies.

BACKGROUND: Pregnancy-related hypertensive disorders, including preeclampsia (PE) and pregnancy-induced hypertension (PIH), may influence the maternal risk of breast cancer. However, results of the cohort studies were inconsistent. METHODS: An updated meta-analysis of cohort studies was performed to evaluate the association between PE, PIH and maternal breast cancer incidence. Relevant studies were identified via searching of PubMed and Embase databases. A random effect model was applied to synthesize the results. Stratified analyses were performed to evaluate the potential influence of parity, gender of offspring, and study design on the association between PE and maternal breast cancer incidence. RESULTS: Ten cohort studies with 2,417,899 pregnant women were included. Maternal risk of breast cancer was not significantly affected by PE (risk ration [RR] = 0.93, 95% confidence interval [CI]: 0.82-1.06, p = .27), or PIH (RR = 0.95, 95% CI: 0.81-1.12, p = .54). Interestingly, PE was associated with significantly lowered maternal incidence of breast cancer in women who give birth to male offspring (RR = 0.79, p < .01), and in those of prospective cohort studies (RR = 0.87, p < .01). However, no significant association between PE and maternal breast cancer was detected in primiparous women, those who gave birth to female offspring, or those of retrospective cohorts. CONCLUSIONS: Current evidence did not support a conclusive association between PE, PIH and the maternal risk of breast cancer. Gender of the offspring may influence the association between PE and maternal breast cancer incidence.

Association of interleukin-12 gene polymorphisms with cancer susceptibility: a meta-analysis.

OBJECTIVE: To evaluate the association between interleukin-12 (IL-12) gene polymorphism and cervical cancer susceptibility. METHODS: We comprehensively retrieved the relevant English and Chinese database to collect case-control studies on the association between the IL-12 gene polymorphism and cervical cancer susceptibility. Data were extracted independently by two researchers respectively, the summary data were analyzed using Revman 5.2 software, the association was described using odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: According to inclusion and exclusion criteria, 5 case-control studies involving 2552 cervical cancer patients and 2232 healthy controls were included. The meta-analysis results showed that 3'UTR+1188 (rs3212227) polymorphism in IL-12 gene was not associated with cervical cancer risk (C vs. A: OR=1.09, 95% CI: 0.88~1.35, P=0.45; AA+AC vs. CC: OR=0.88, 95% CI: 0.67~1.15, P=0.34; AA vs. AC+CC: OR=0.89. 95% CI: 0.56-1.42, P=0.62; CC vs. AA: OR=1.30. 95% CI: 0.79-2.12, P=0.30). CONCLUSION: The available evidence suggested that rs3212227 polymorphism in IL-12 gene may not be the risk factor to cervical cancer.