The murine meninges acquire lymphoid tissue properties and harbour autoreactive B cells during chronic <i>Trypanosoma brucei</i> infection

The meningeal space is a critical brain structure providing immunosurveillance for the central nervous system (CNS), but the impact of infections on the meningeal immune landscape is far from being fully understood. The extracellular protozoan parasite Trypanosoma brucei, which causes human African trypanosomiasis (HAT) or sleeping sickness, accumulates in the meningeal spaces, ultimately inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, by combining single-cell transcriptomics and mass cytometry by time-of-flight (CyTOF) with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges. These infection-induced ELAs were defined by the presence of ER-TR7+ fibroblastic reticular cells, CD21/35+ follicular dendritic cells (FDCs), CXCR5+ PD1+ T follicular helper-like phenotype, GL7+ CD95+ GC-like B cells, and plasmablasts/plasma cells. Furthermore, the B cells found in the infected meninges produced high-affinity autoantibodies able to recognise mouse brain antigens, in a process dependent on LTβ signalling. A mid-throughput screening identified several host factors recognised by these autoantibodies, including myelin basic protein (MBP), coinciding with cortical demyelination and brain pathology. In humans, we identified the presence of autoreactive IgG antibodies in the cerebrospinal fluid (CSF) of second stage HAT patients that recognised human brain lysates and MBP, consistent with our findings in experimental infections. Lastly, we found that the pathological B cell responses we observed in the meninges required the presence of T. brucei in the CNS, as suramin treatment before the onset of the CNS stage prevented the accumulation of GL7+ CD95+ GC-like B cells and brain-specific autoantibody deposition. Taken together, our data provide evidence that the meningeal immune response during chronic T. brucei infection results in the acquisition of lymphoid tissue-like properties, broadening our understanding of meningeal immunity in the context of chronic infections. These findings have wider implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity in mice and humans, as observed in other autoimmune neurodegenerative disorders, including neuropsychiatric lupus and multiple sclerosis.</p

Interim data monitoring to enroll higher-risk participants in HIV prevention trials

<p>Abstract</p> <p>Background</p> <p>Lower-than-expected incidence of HIV undermines sample size calculations and compromises the power of a HIV prevention trial. We evaluated the effectiveness of interim monitoring of HIV infection rates and on-going modification of recruitment strategies to enroll women at higher risk of HIV in the Cellulose Sulfate Phase III study in Nigeria.</p> <p>Methods</p> <p>We analyzed prevalence and incidence of HIV and other sexually transmitted infections, demographic and sexual behavior characteristics aggregated over the treatment groups on a quarterly basis. The site investigators were advised on their recruitment strategies based on the findings of the interim analyses.</p> <p>Results</p> <p>A total of 3619 women were screened and 1644 enrolled at the Ikeja and Apapa clinics in Lagos, and at the Central and Peripheral clinics in Port Harcourt. Twelve months after study initiation, the overall incidence of HIV was less than one-third of the pre-study assumption, with rates of HIV that varied substantially between clinics. Due to the low prevalence and incidence rates of HIV, it was decided to close the Ikeja clinic in Lagos and to find new catchment areas in Port Harcourt. This strategy was associated with an almost two-fold increase in observed HIV incidence during the second year of the study.</p> <p>Conclusion</p> <p>Given the difficulties in estimating HIV incidence, a close monitoring of HIV prevalence and incidence rates during a trial is warranted. The on-going modification of recruitment strategies based on the regular analysis of HIV rates appeared to be an efficient method for targeting populations at greatest risk of HIV infection and increasing study power in the Nigeria trial.</p> <p>Trial Registration</p> <p>The trial was registered with the ClinicalTrials.gov registry under #NCT00120770 <url>http://clinicaltrials.gov/ct2/show/NCT00120770</url></p

γδ T cells control murine skin inflammation and subcutaneous adipose wasting during chronic Trypanosoma brucei infection

African trypanosomes colonise the skin to ensure parasite transmission. However, how the skin responds to trypanosome infection remains unresolved. Here, we investigate the local immune response of the skin in a murine model of infection using spatial and single cell transcriptomics. We detect expansion of dermal IL-17A-producing Vγ6+ cells during infection, which occurs in the subcutaneous adipose tissue. In silico cell-cell communication analysis suggests that subcutaneous interstitial preadipocytes trigger T cell activation via Cd40 and Tnfsf18 signalling, amongst others. In vivo, we observe that female mice deficient for IL-17A-producing Vγ6+ cells show extensive inflammation and limit subcutaneous adipose tissue wasting, independently of parasite burden. Based on these observations, we propose that subcutaneous adipocytes and Vγ6+ cells act in concert to limit skin inflammation and adipose tissue wasting. These studies provide new insights into the role of γδ T cell and subcutaneous adipocytes as homeostatic regulators of skin immunity during chronic infection

Effectiveness of Cellulose Sulfate Vaginal Gel for the Prevention of HIV Infection: Results of a Phase III Trial in Nigeria

BACKGROUND: This trial evaluated the safety and effectiveness of 6% cellulose sulfate vaginal gel in preventing male-to-female vaginal transmission of HIV, gonorrhea and chlamydial infection. METHODS: This Phase III, double-blind, randomized, placebo-controlled trial was conducted between November 2004 and March 2007 in Lagos and Port Harcourt, Nigeria. We enrolled 1644 HIV-antibody negative women at high risk of HIV acquisition. Study participants were randomized 1:1 to cellulose sulfate or placebo and asked to use gel plus a condom for each act of vaginal intercourse over one year of follow-up. The participants were evaluated monthly for HIV, gonorrhea and chlamydial infection, and for adverse events. RESULTS: The trial was stopped prematurely after the data safety monitoring board of a parallel trial concluded that cellulose sulfate might be increasing the risk of HIV. In contrast, we observed fewer infections in the active arm (10) than on placebo (13), a difference that was nonetheless not statistically significant (HR = 0.8, 95% CI 0.3-1.8; p = 0.56). Rates of gonorrhea and chlamydial infection were lower in the CS group but the difference was likewise not statistically significant (HR = 0.8, 95% CI 0.5-1.1; p = 0.19 for the combined STI outcome). Rates of adverse events were similar across study arms. No serious adverse events related to cellulose sulfate use were reported. CONCLUSIONS: Cellulose sulfate gel appeared to be safe in the evaluated study population but we found insufficient evidence that it prevented male-to-female vaginal transmission of HIV, gonorrhea or chlamydial infection. The early closure of the trial compromised the ability to draw definitive conclusions about the effectiveness of cellulose sulfate against HIV. TRIAL REGISTRATION: ClinicalTrials.gov NCT00120770

Publisher Correction: IL-17 signalling is critical for controlling subcutaneous adipose tissue dynamics and parasite burden during chronic murine Trypanosoma brucei infection.

Correction to: Nature Communications https://doi.org/10.1038/s41467-023-42918-8, published online 03 November 2023

From Ebola to COVID-19: emergency preparedness and response plans and actions in Lagos, Nigeria

Background Lagos state is the industrial nerve centre of Nigeria and was the epicentre of the 2014 Ebola outbreak in Nigeria as it is now for the current Coronavirus Disease (COVID-19) outbreak. This paper describes how the lessons learned from the Ebola outbreak in 2014 informed the emergency preparedness of the State ahead of the COVID-19 outbreak and guided response. Discussion Following the Ebola outbreak in 2014, the Lagos State government provided governance by developing a policy on emergency preparedness and biosecurity and provided oversight and coordination of emergency preparedness strategies. Capacities for emergency response were strengthened by training key staff, developing a robust surveillance system, and setting up a Biosafety Level 3 laboratory and biobank. Resource provision, in terms of finances and trained personnel for emergencies was prioritized by the government. With the onset of COVID-19, Lagos state was able to respond promptly to the outbreak using the centralized Incident Command Structure and the key activities of the Emergency Operations Centre. Contributory to effective response were partnerships with the private sectors, community engagement and political commitment. Conclusion Using the lessons learned from the 2014 Ebola outbreak, Lagos State had gradually prepared its healthcare system for a pandemic such as COVID-19. The State needs to continue to expand its preparedness to be more resilient and future proof to respond to disease outbreaks. Looking beyond intra-state gains, lessons and identified best practices from the past and present should be shared with other states and countries

From Ebola to COVID-19: emergency preparedness and response plans and actions in Lagos, Nigeria

BACKGROUND: Lagos state is the industrial nerve centre of Nigeria and was the epicentre of the 2014 Ebola outbreak in Nigeria as it is now for the current Coronavirus Disease (COVID-19) outbreak. This paper describes how the lessons learned from the Ebola outbreak in 2014 informed the emergency preparedness of the State ahead of the COVID-19 outbreak and guided response. DISCUSSION: Following the Ebola outbreak in 2014, the Lagos State government provided governance by developing a policy on emergency preparedness and biosecurity and provided oversight and coordination of emergency preparedness strategies. Capacities for emergency response were strengthened by training key staff, developing a robust surveillance system, and setting up a Biosafety Level 3 laboratory and biobank. Resource provision, in terms of finances and trained personnel for emergencies was prioritized by the government. With the onset of COVID-19, Lagos state was able to respond promptly to the outbreak using the centralized Incident Command Structure and the key activities of the Emergency Operations Centre. Contributory to effective response were partnerships with the private sectors, community engagement and political commitment. CONCLUSION: Using the lessons learned from the 2014 Ebola outbreak, Lagos State had gradually prepared its healthcare system for a pandemic such as COVID-19. The State needs to continue to expand its preparedness to be more resilient and future proof to respond to disease outbreaks. Looking beyond intra-state gains, lessons and identified best practices from the past and present should be shared with other states and countries

Relationship between resistance to African trypanosomiasis and development of chronic kidney disease

Abstract not currently available