Alveolar T-helper 17 responses to streptococcus pneumoniae are preserved in ART-untreated and treated HIV-infected Malawian adults

Objective: We explored if HIV infection is associated with impaired T-Helper 17 responses against Streptococcus pneumoniae in the lung. Methods: We recruited 30 HIV-uninfected healthy controls, 23 asymptomatic HIV-infected adults not on ART, and 40 asymptomatic HIV-infected adults on ART (Median time 3.5yrs), in whom we collected bronchoalveolar lavage fluid. We measured alveolar CD4+ T cell immune responses following stimulation with pneumococcal cell culture supernatant using flow cytometry-based intracellular cytokine staining. Results: We found that the proportion of alveolar CD4+ T cells producing IL-17A following stimulation with pneumococcal cell culture supernatant (CCS) was similar between HIV-uninfected controls and ART-naïve HIV-infected adults (0.10% vs. 0.14%; p = 0.9273). In contrast, the proportion and relative absolute counts of CD4+ T cells producing IL-17A in response to pneumococcal CCS were higher in ART-treated HIV-infected adults compared HIV-uninfected controls (0.22% vs. 0.10%, p = 0.0166; 5420 vs. 1902 cells/100 ml BAL fluid; p = 0.0519). The increase in relative absolute numbers of IL-17A-producing alveolar CD4+ T cells in ART-treated individuals was not correlated with the peripheral blood CD4+ T cell count (r=–0.1876, p = 0.1785). Conclusion: Alveolar Th17 responses against S. pneumoniae are preserved in HIV-infected adults. This suggests that there are other alternative mechanisms that are altered in HIV-infected individuals that render them more susceptible to pneumococcal pneumonia

Structural and phenotypic analysis of Chikungunya virus RNA replication elements

Chikungunya virus (CHIKV) is a re-emerging, pathogenic Alphavirus transmitted to humans by Aedes spp. mosquitoes. We have mapped the RNA structure of the 5′ region of the CHIKV genome using selective 2′-hydroxyl acylation analysed by primer extension (SHAPE) to investigate intramolecular base-pairing at single-nucleotide resolution. Taking a structure-led reverse genetic approach, in both infectious virus and sub-genomic replicon systems, we identified six RNA replication elements essential to efficient CHIKV genome replication - including novel elements, either not previously analysed in other alphaviruses or specific to CHIKV. Importantly, through a reverse genetic approach we demonstrate that the replication elements function within the positive-strand genomic copy of the virus genome, in predominantly structure-dependent mechanisms during efficient replication of the CHIKV genome. Comparative analysis in human and mosquito-derived cell lines reveal that a novel element within the 5′UTR is essential for efficient replication in both host systems, while those in the adjacent nsP1 encoding region are specific to either vertebrate or invertebrate host cells. In addition to furthering our knowledge of fundamental aspects of the molecular virology of this important human pathogen, we foresee that results from this study will be important for rational design of a genetically stable attenuated vaccine

Relative costs and effectiveness of treating uncomplicated malaria in two rural districts in Zambia: implications for nationwide scale-up of home-based management

<p>Abstract</p> <p>Background</p> <p>Malaria case management is one of the key strategies to control malaria. Various studies have demonstrated the feasibility of home management of malaria (HMM). However, data on the costs and effectiveness of artemisinin-based combination therapy (ACT) and rapid diagnostic tests via HMM is limited.</p> <p>Method</p> <p>Cost-effectiveness of home management versus health facility-based management of uncomplicated malaria in two rural districts in Zambia was analysed from a providers' perspective. The sample included 16 community health workers (CHWs) and 15 health facilities. The outcome measure was the cost per case appropriately diagnosed and treated. Costs of scaling-up HMM nationwide were estimated based on the CHW utilisation rates observed in the study.</p> <p>Results</p> <p>HMM was more cost effective than facility-based management of uncomplicated malaria. The cost per case correctly diagnosed and treated was USD 4.22 for HMM and USD 6.12 for facility level. Utilization and adherence to diagnostic and treatment guidelines was higher in HMM than at a health facility.</p> <p>Conclusion</p> <p>HMM using ACT and RDTs was more efficient at appropriately diagnosing and treating malaria than the health facility level. Scaling up this intervention requires significant investments.</p

Critical Loss of the Balance between Th17 and T Regulatory Cell Populations in Pathogenic SIV Infection

Chronic immune activation and progression to AIDS are observed after SIV infection in macaques but not in natural host primate species. To better understand this dichotomy, we compared acute pathogenic SIV infection in pigtailed macaques (PTs) to non-pathogenic infection in African green monkeys (AGMs). SIVagm-infected PTs, but not SIVagm-infected AGMs, rapidly developed systemic immune activation, marked and selective depletion of IL-17-secreting (Th17) cells, and loss of the balance between Th17 and T regulatory (Treg) cells in blood, lymphoid organs, and mucosal tissue. The loss of Th17 cells was found to be predictive of systemic and sustained T cell activation. Collectively, these data indicate that loss of the Th17 to Treg balance is related to SIV disease progression

Vulnerable newborn types: analysis of subnational, population-based birth cohorts for 541 285 live births in 23 countries, 2000-2021.

OBJECTIVE: To examine prevalence of novel newborn types among 541 285 live births in 23 countries from 2000 to 2021. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Subnational, population-based birth cohort studies (n = 45) in 23 low- and middle-income countries (LMICs) spanning 2000-2021. POPULATION: Liveborn infants. METHODS: Subnational, population-based studies with high-quality birth outcome data from LMICs were invited to join the Vulnerable Newborn Measurement Collaboration. We defined distinct newborn types using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight, LBW [<2500 g], nonLBW) as ten types (using all three outcomes), six types (by excluding the birthweight categorisation), and four types (by collapsing the AGA and LGA categories). We defined small types as those with at least one classification of LBW, PT or SGA. We presented study characteristics, participant characteristics, data missingness, and prevalence of newborn types by region and study. RESULTS: Among 541 285 live births, 476 939 (88.1%) had non-missing and plausible values for gestational age, birthweight and sex required to construct the newborn types. The median prevalences of ten types across studies were T+AGA+nonLBW (58.0%), T+LGA+nonLBW (3.3%), T+AGA+LBW (0.5%), T+SGA+nonLBW (14.2%), T+SGA+LBW (7.1%), PT+LGA+nonLBW (1.6%), PT+LGA+LBW (0.2%), PT+AGA+nonLBW (3.7%), PT+AGA+LBW (3.6%) and PT+SGA+LBW (1.0%). The median prevalence of small types (six types, 37.6%) varied across studies and within regions and was higher in Southern Asia (52.4%) than in Sub-Saharan Africa (34.9%). CONCLUSIONS: Further investigation is needed to describe the mortality risks associated with newborn types and understand the implications of this framework for local targeting of interventions to prevent adverse pregnancy outcomes in LMICs

HIV-associated disruption of lung cytokine networks is incompletely restored in asymptomatic HIV-infected Malawian adults on antiretroviral therapy.

Disruption of lung cytokine networks during chronic HIV infection is incompletely restored in individuals on antiretroviral therap