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In the past decade, research on the functions of extracellular vesicles in malaria has expanded dramatically. Investigations into the various vesicle types, from both host and parasite origin, has revealed important roles for extracellular vesicles in disease pathogenesis and susceptibility, as well as cell–cell communication and immune responses. Here, work relating to extracellular vesicles in malaria is reviewed, and the areas that remain unknown and require further investigations are highlighted.

STING is an innate immune cytosolic adaptor for DNA sensors that engage malaria parasite ( Plasmodium falciparum ) or other pathogen DNA. As P. falciparum infects red blood cells and not leukocytes, how parasite DNA reaches such host cytosolic DNA sensors in immune cells is unclear. Here we show that malaria parasites inside red blood cells can engage host cytosolic innate immune cell receptors from a distance by secreting extracellular vesicles (EV) containing parasitic small RNA and genomic DNA. Upon internalization of DNA-harboring EVs by human monocytes, P. falciparum DNA is released within the host cell cytosol, leading to STING-dependent DNA sensing. STING subsequently activates the kinase TBK1, which phosphorylates the transcription factor IRF3, causing IRF3 to translocate to the nucleus and induce STING-dependent gene expression. This DNA-sensing pathway may be an important decoy mechanism to promote P. falciparum virulence and thereby may affect future strategies to treat malaria. STING is an intracellular DNA sensor that can alter response to infection, but in the case of malaria it is unclear how parasite DNA in red blood cells (RBCs) reaches DNA sensors in immune cells. Here the authors show that STING in human monocytes can sense P. falciparum nucleic acids transported from infected RBCs via parasite extracellular vesicles.

To protect healthcare workforce during the COVID-19 pandemic, rigorous efforts were made to reduce infection rates among healthcare workers (HCWs), especially prior to vaccine availability. This study aimed to investigate the prevalence of SARS-CoV-2 infections among HCWs and identify potential risk factors associated with transmission. We searched MEDLINE, Embase, and Google Scholar from 1 December 2019 to 5 February 2024. From 498 initial records, 190 articles were reviewed, and 63 studies were eligible. ROBINS-E tool revealed a lower risk of bias in several domains; however, some concerns related to confounding and exposure measurement were identified. Globally, 11% (95% confidence interval (CI) 9–13) of 283,932 HCWs were infected with SARS-CoV-2. Infection rates were associated with a constellation of risk factors and major circulating SARS-CoV-2 variants. Household exposure (odds ratio (OR) 7.07; 95% CI 3.93–12.73), working as a cleaner (OR 2.72; 95% CI 1.39–5.32), occupational exposure (OR 1.79; 95% CI 1.49–2.14), inadequate training on infection prevention and control (OR 1.46; 95% CI 1.14–1.87), insufficient use of personal protective equipment (OR 1.45; 95% CI 1.14–1.84), performing aerosol generating procedures (OR 1.36; 95% CI 1.21–1.52) and inadequate hand hygiene (OR 1.17; 95% CI 0.79–1.73) were associated with an increased SARS-CoV-2 infection. Conversely, history of quarantine (OR 0.23; 95% CI 0.08–0.60) and frequent decontamination of high touch areas (OR 0.52; 95% CI 0.42–0.64) were protective factors against SARS-CoV-2 infection. This study quantifies the substantial global burden of SARS-CoV-2 infection among HCWs. We underscore the urgent need for effective infection prevention and control measures, particularly addressing factors such as household exposure and occupational practices by HCWs, including cleaning staff.

Background A firm understanding of SARS-CoV-2 hybrid immunity is crucial for our ongoing efforts to protect people from severe and fatal disease and assess population vulnerability to emerging novel variants. As many components of the immune response are unobserved and complex to investigate, some ambiguities and unanswered questions remain about hybrid immunity to COVID-19, such as the duration of the antibody response in individuals. Methods To address this, we evaluated longitudinal data that spanned up to 21 months from 52 SARS-CoV-2 naive individuals and 88 SARS-CoV-2 recovered individuals. We further separated individuals according to whether they received an mRNA or non-mRNA vaccine for their primary two-dose vaccinations. A hierarchical Bayesian framework was used to fit the parameters of mono-phasic exponential decay and bi-phasic exponential decay models to the observed data to estimate the magnitude and half-life of the spike-specific and receptor-binding domain (RBD)-specific IgG responses. Results Results from both our mono-phasic and bi-phasic exponential decay models estimate that the median half-life of the spike-specific and RBD-specific IgG response in individuals with hybrid immunity is almost double that of naive individuals who were only vaccinated. Recovered mRNA recipients were estimated through the mono-phasic decay model to have a median IgG response half-life of 448 days (95% CrI: [375.08, 547.54]) to spike antigen, compared to an estimated 222 days (95% CrI: [179.90, 286.62]) for naive mRNA recipients. Posterior estimates from the bi-phasic exponential decay model show that recovered individuals who received mRNA vaccinations had a median IgG response half-life of 810 days (95% CrI: [650.91, 1031.63]) to spike antigen, compared to 451 days (95% CrI: [336.81, 618.14]) for naive mRNA recipients. A similar pattern is seen in non-mRNA vaccine recipients, with IgG response half-lives differing slightly. Our results show that, across different model assumptions, individuals with hybrid immunity have an IgG response half-life that is considerably greater than that of individuals with only infection- or vaccine-induced immunity. Conclusions Our work provides important insight into the longevity of the IgG response to SARS-CoV-2 in individuals with hybrid immunity and can guide effective immunisation approaches to maintain and improve population-level protection.

COVID-19 clinical presentation differs considerably between individuals, ranging from asymptomatic, mild/moderate and severe disease which in some cases are fatal or result in long-term effects. Identifying immune mechanisms behind severe disease development informs screening strategies to predict who are at greater risk of developing life-threatening complications. However, to date clear prognostic indicators of individual risk of severe or long COVID remain elusive. Autoantibodies recognize a range of self-antigens and upon antigen recognition and binding, important processes involved in inflammation, pathogen defence and coagulation are modified. Recent studies report a significantly higher prevalence of autoantibodies that target immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins in COVID-19 patients experiencing severe disease compared to those who experience mild or asymptomatic infections. Here we discuss the diverse impacts of autoantibodies on immune processes and associations with severe COVID-19 disease.

Toll like receptors (TLRs) are important pattern recognition receptors that can detect pathogen and danger associated molecular patterns to initiate an innate immune response. TLR1 and 2 heterodimerize at the plasma membrane upon binding to triacylated lipopeptides from bacterial cell walls, or to the synthetic ligand Pam3CSK4. TLR1/2 dimers interact with adaptor molecules TIRAP and MyD88 to initiate a signalling cascade that leads to activation of key transcription factors, including NF-kB. Despite TLRs being extensively studied over the last two decades, the real-time kinetics of ligand binding and receptor activation remains largely unexplored. We aimed to study the kinetics of TLR activation and recruitment of adaptors, using TLR1/2 dimer interactions with adaptors MyD88 and TIRAP. Bioluminescence resonance energy transfer (BRET) allows detection of real-time protein-protein interactions in living cells, and was applied to study adaptor recruitment to TLRs. Energy transfer showed interactions between TLR2 and TIRAP, and between TLR2 and MyD88 only in the presence of TIRAP. Quantitative BRET and confocal microscopy confirmed that TIRAP is necessary for MyD88 interaction with TLR2. Furthermore, constitutive proximity between the proteins in the absence of Pam3CSK4 stimulation was observed with BRET, and was not abrogated with lowered protein expression, changes in protein tagging strategies, or use of the brighter NanoLuc luciferase. However, co-immunoprecipitation studies did not demonstrate constitutive interaction between these proteins, suggesting that the interaction observed with BRET likely represents artefacts of protein overexpression. Thus, caution should be taken when utilizing protein overexpression in BRET studies and in investigations of the TLR pathway.

Naturally acquired humoral immunity to the malarial parasite Plasmodium falciparum can protect against disease, although the precise mechanisms remain unclear. Although antibody levels can be measured by ELISA, few studies have investigated functional antibody assays in relation to clinical outcomes. In this study we applied a recently developed functional assay of antibody-mediated opsonisation of merozoites, to plasma samples from a longitudinal cohort study conducted in a malaria endemic region of Papua New Guinea (PNG). Phagocytic activity was quantified by flow cytometry using a standardized and high-throughput protocol, and was subsequently evaluated for association with protection from clinical malaria and high-density parasitemia. Opsonising antibody responses were found to: i) increase with age, ii) be enhanced by concurrent infection, and iii) correlate with protection from clinical episodes and high-density parasitemia. Stronger protective associations were observed in individuals with no detectable parasitemia at baseline. This study presents the first evidence for merozoite phagocytosis as a correlate of acquired immunity and clinical protection against P. falciparum malaria.

Studies on binding and neutralizing antibody responses to COVID-19 vaccines and breakthrough infections were frequently confounded by unsuspected exposure to intercurrent natural infections with SARS-CoV-2 in the community particularly during year 1 and 2 of the pandemic. This study is extraordinary in that it was conducted in Australia, where SARS-CoV-2 circulation was largely contained by public health and social measures for the first 2 years of the pandemic. We followed well-defined study populations who received vaccines in a natural infection-free setting or a separate subgroup who had natural infection. Thus, the study provides unique insights in infection-naïve, vaccinated individuals and those with breakthrough infections with Omicron variants. In this setting, we had an opportunity to demonstrate evidence of antigenic imprinting, with neutralizing antibody responses to the ancestral vaccine antigen being higher than responses to the infecting Omicron variant.

Background Typical symptoms of uncomplicated dengue fever (DF) include headache, muscle pains, rash, cough, and vomiting. A proportion of cases progress to severe dengue hemorrhagic fever (DHF), associated with increased vascular permeability, thrombocytopenia, and hemorrhages. Progression to severe dengue is difficult to diagnose at the onset of fever, which complicates patient triage, posing a socio-economic burden on health systems. Methods To identify parameters associated with protection and susceptibility to DHF, we pursued a systems immunology approach integrating plasma chemokine profiling, high-dimensional mass cytometry and peripheral blood mononuclear cell (PBMC) transcriptomic analysis at the onset of fever in a prospective study conducted in Indonesia. Results After a secondary infection, progression to uncomplicated dengue featured transcriptional profiles associated with increased cell proliferation and metabolism, and an expansion of ICOS + CD4 + and CD8 + effector memory T cells. These responses were virtually absent in cases progressing to severe DHF, that instead mounted an innate-like response, characterised by inflammatory transcriptional profiles, high circulating levels of inflammatory chemokines and with high frequencies of CD4 low non-classical monocytes predicting increased odds of severe disease. Conclusions Our results suggests that effector memory T cell activation might play an important role ameliorating severe disease symptoms during a secondary dengue infection, and in the absence of that response, a strong innate inflammatory response is required to control viral replication. Our research also identified discrete cell populations predicting increased odds of severe disease, with potential diagnostic value.

ObjectiveTo investigate whether IgG to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens could reveal undetected SARS-CoV-2 exposure in a cohort of Malawian pregnant women participating in the REVAMP clinical trial.DesignA secondary analysis of serological samples from a randomised controlled trial of iron supplementation in pregnancy, which began recruiting women in November 2018 and had its last visit occurring in September 2021.SettingResource-limited setting in Zomba and Blantyre, Southern Malawi.ParticipantsPregnant women with ultrasound-confirmed singleton pregnancies in the second trimester, with haemoglobin <100 g/L and randomised at enrolment to receive either intravenous ferric carboxymaltose or standard oral iron, where no coronavirus disease 2019 (COVID-19) clinical cases or SARS-CoV-2 positive tests were reported during the pandemic (April 2020–September 2021).Primary and secondary outcomesPrimary outcome was the levels of antibodies and seropositivity to SARS-CoV-2 antigens in the cohort of women across the duration of the trial. Secondary outcomes were the impact of IgG levels and seropositivity to SARS-CoV-2 on pregnancy outcomes.ResultsAt delivery, IgG levels to SARS-CoV-2 antigens increased sharply by 18.5%–29.7% every 30 days during COVID-19 waves 2 and 3. Overall seropositivity reached 39.3% during the pandemic; however, 14.7% pre-pandemic seropositivity demonstrates cross-reactive antibody responses. Pandemic pregnancies showed improved outcomes with longer gestations (mean difference: 0.6 weeks (95% CI 0.2 to 0.9)) and higher birth weights (mean difference: 169.3 g (65.9–272.6)). SARS-CoV-2 IgG levels were not associated with pregnancy outcomes.ConclusionSerological testing was able to detect exposure to SARS-CoV-2 in a population without clinical indications of the disease, suggesting that serosurveillance is more sensitive than relying on clinical data to monitor pathogen exposure in the community. Additionally, this highlights pregnancy cohorts as valuable sentinel populations for infectious disease surveillance in resource-limited settings.Trial registration numberThis trial was prospectively registered at ANZCTR: ACTRN12618001268235.