Prevalence of micronutrient deficiencies across diverse environments in rural Madagascar.

It is estimated that billions of people around the world are affected by micronutrient deficiencies. Madagascar is considered to be particularly nutritionally vulnerable, with nearly half of the population stunted, and parts of the country facing emergency, near famine-like conditions (IPC4). Although Madagascar is generally considered among the most undernourished of countries, empirical data in the form of biological samples to validate these claims are extremely limited. Our research drew data from three studies conducted between 2013-2020 and provided comprehensive biomarker profile information for 4,710 individuals from 30 communities in five different ecological regions during at least one time-point. Estimated prevalences of nutrient deficiencies and inflammation across various regions of rural Madagascar were of concern for both sexes and across all ages, with 66.5% of the population estimated to be deficient in zinc, 15.6% depleted in vitamin B12 (3.6% deficient), 11.6% deficient in retinol, and lower levels of iron deficiency (as indicated by 11.7% deficient in ferritin and 2.3% deficient assessed by soluble transferrin receptors). Beyond nutrient status biomarkers, nearly one quarter of the population (24.0%) exhibited chronic inflammation based on high values of α-1-acid glycoprotein, and 12.3% exhibited acute inflammation based on high values of C-reactive protein. There is an 8-fold difference between the lowest and highest regional observed prevalence of vitamin B12 deficiency, a 10-fold difference in vitamin A deficiency (based on retinol), and a 2-fold difference in acute inflammation (CRP) and deficiencies of zinc and iron (based on ferritin), highlighting strong geographical variations in micronutrient deficiencies across Madagascar.

Assessing the impact of preventative measures to limit the spread of Toxoplasma gondii in wild carnivores of Madagascar.

Novel multihost pathogens can threaten endangered wildlife species, as well as humans and domestic animals. The zoonotic protozoan parasite Toxoplasma gondii is transmitted by members of Felidae and can infect a large number of animal species, including humans. This parasite can have significant health consequences for infected intermediate hosts and could further endanger wild carnivore populations of Madagascar. Building on an empirical characterization of the prevalence of the pathogen in local mammals, we used mathematical models of pathogen transmission in a multihost community to compare preventative measures that aim to limit the spread of this parasite in wild carnivores. Specifically, we examined the effect of hypothetical cat vaccination and population control campaigns on reducing the risk of infection by T. gondii in wild Eupleridae. Our model predicted that the prevalence of exposure to T. gondii in cats would be around 72% and that seroprevalence would reach 2% and 43% in rodents and wild carnivores, respectively. Reducing the rodent population in the landscape by half may only decrease the prevalence of T. gondii in carnivores by 10%. Similarly, cat vaccination and reducing the population of definitive hosts had limited impact on the prevalence of T. gondii in wild carnivorans of Madagascar. A significant reduction in prevalence would require extremely high vaccination, low turnover, or both in the cat population. Other potential control methods of T. gondii in endangered Eupleridae include targeted vaccination of wild animals but would require further investigation. Eliminating the threat entirely will be difficult because of the ubiquity of cats and the persistence of the parasite in the environment.

Evaluación del impacto de las medidas preventivas para limitar el contagio de Toxoplasma gondii en los carnívoros silvestres de Madagascar Resumen Los patógenos novedosos con múltiples hospederos pueden amenazar tanto a las especies silvestres como a los humanos y a los animales domésticos. Los miembros de la familia Felidae transmiten el protozoario parásito Toxoplasma gondii, el cual puede infectar a un gran número de especies animales, incluyendo al humano. Este parásito puede generar consecuencias importantes para la salud en los hospederos intermediarios infectados y podría poner más en peligro a las poblaciones de carnívoros silvestres de Madagascar. Usamos modelos matemáticos de la transmisión de patógenos en una comunidad con múltiples hospederos a partir de una caracterización empírica de la prevalencia del patógeno en los mamíferos locales para comparar las medidas preventivas que buscan limitar la transmisión de este parásito en los carnívoros silvestres. En específico, examinamos el efecto de la vacunación hipotética de felinos y las campañas de control poblacional sobre la reducción del riesgo de infección de T. gondii en los Eupleridae silvestres. Nuestro modelo predijo que la prevalencia de la exposición a T. gondii en los felinos sería de un 72% y que la seroprevalencia llegaría al 2% y al 43% en los roedores y carnívoros silvestres, respectivamente. La reducción a la mitad de la población de roedores en el paisaje podría disminuir sólo en un 10% la prevalencia del protozoario en los carnívoros. De forma similar, la vacunación y la reducción de la población de hospederos definitivos tuvieron un impacto limitado sobre la prevalencia de T. gondii en los carnívoros silvestres de Madagascar. Una reducción significativa en la prevalencia requeriría que la población de felinos tuviera una vacunación extremadamente elevada, baja rotación, o ambas. Otros métodos potenciales de control de T. gondii en los Eupleridae incluyen la vacunación de animales silvestres, pero requieren de mayor investigación. La eliminación completa de la amenaza será difícil por la ubicuidad de los felinos y la persistencia del parásito en el ambiente.

The impact of sub-national heterogeneities in demography and epidemiology on the introduction of rubella vaccination programs in Nigeria.

Rubella infection during pregnancy can result in miscarriage or infants with a constellation of birth defects known as congenital rubella syndrome (CRS). When coverage is inadequate, rubella vaccination can increase CRS cases by increasing the average age of infection. Thus, the World Health Organisation recommends that countries introducing rubella vaccine be able to vaccinate at least 80% of each birth cohort. Previous studies have focused on national-level analyses and have overlooked sub-national variation in introduction risk. We characterised the sub-national heterogeneity in rubella transmission within Nigeria and modelled local rubella vaccine introduction under different scenarios to refine the set of conditions and strategies required for safe rubella vaccine use. Across Nigeria, the basic reproduction number ranged from 2.6 to 6.2. Consequently, the conditions for safe vaccination varied across states with low-risk areas requiring coverage levels well below 80 %. In high-risk settings, inadequate routine coverage needed to be supplemented by campaigns that allowed for gradual improvements in vaccination coverage over time. Understanding local heterogeneities in both short-term and long-term epidemic dynamics can permit earlier nationwide introduction of rubella vaccination and identify sub-national areas suitable for program monitoring, program improvement and campaign support.

Inferring COVID-19 testing and vaccination behavior from New Jersey testing data.

Characterizing the relationship between disease testing behaviors and infectious disease dynamics is of great importance for public health. Tests for both current and past infection can influence disease-related behaviors at the individual level, while population-level knowledge of an epidemic's course may feed back to affect one's likelihood of taking a test. The COVID-19 pandemic has generated testing data on an unprecedented scale for tests detecting both current infection (PCR, antigen) and past infection (serology); this opens the way to characterizing the complex relationship between testing behavior and infection dynamics. Leveraging a rich database of individualized COVID-19 testing histories in New Jersey, we analyze the behavioral relationships between PCR and serology tests, infection, and vaccination. We quantify interactions between individuals' test-taking tendencies and their past testing and infection histories, finding that PCR tests were disproportionately taken by people currently infected, and serology tests were disproportionately taken by people with past infection or vaccination. The effects of previous positive test results on testing behavior are less consistent, as individuals with past PCR positives were more likely to take subsequent PCR and serology tests at some periods of the epidemic time course and less likely at others. Lastly, we fit a model to the titer values collected from serology tests to infer vaccination trends, finding a marked decrease in vaccination rates among individuals who had previously received a positive PCR test. These results exemplify the utility of individualized testing histories in uncovering hidden behavioral variables affecting testing and vaccination.

Markets as drivers of selection for highly virulent poultry pathogens.

Theoretical models have successfully predicted the evolution of poultry pathogen virulence in industrialized farm contexts of broiler chicken populations. Whether there are ecological factors specific to more traditional rural farming that affect virulence is an open question. Within non-industrialized farming networks, live bird markets are known to be hotspots of transmission, but whether they could shift selection pressures on the evolution of poultry pathogen virulence has not been addressed. Here, we revisit predictions for the evolution of virulence for viral poultry pathogens, such as Newcastle's disease virus, Marek's disease virus, and influenza virus, H5N1, using a compartmental model that represents transmission in rural markets. We show that both the higher turnover rate and higher environmental persistence in markets relative to farms could select for higher optimal virulence strategies. In contrast to theoretical results modeling industrialized poultry farms, we find that cleaning could also select for decreased virulence in the live poultry market setting. Additionally, we predict that more virulent strategies selected in markets could circulate solely within poultry located in markets. Thus, we recommend the close monitoring of markets not only as hotspots of transmission, but as potential sources of more virulent strains of poultry pathogens.

Engaging multisector stakeholders to identify priorities for global health innovation, change and research: an engagement methodology and application to prosthetics service delivery in Cambodia.

PURPOSE: While innovation is known to catalyse solutions to global sustainable development challenges, lack of engagement from stakeholders during conceptualisation and development may influence the degree of success of implementation. METHODS AND MATERIALS: This paper presents a complete and novel engagement methodology, developed from value led business modelling approaches, for working with multi-sector stakeholders. The methodology can be used to determine barriers and facilitators to clinical practice innovations or translational research, within a country-specific context. The approach has then been applied in the Cambodian prosthetics and orthotics sector to provide a practice-based exemplar application of the framework. RESULTS: This approach seeks to ensure the suitability and sustainability of clinical practice and research programmes being implemented within a complex ecosystem. A theoretical basis, drawn from academic and business innovation sectors, has been consolidated and adapted for practical application to design, direct, and inform initiatives in low resource settings. CONCLUSIONS: The methods presented provide a way to both develop and articulate the mission, vision, and goals of any proposed change, and to effectively communicate these with stakeholders in a way that engages the personal and professional values that exist in their ecosystem. It provides a structured process through which meaningful conversations can happen, and a basis for relationship management with key stakeholders; intrinsic to enable a sustained legacy from research and development.

The engagement from stakeholders during conceptualisation and throughout development can determine the success, or not, of any implementation and scale of innovation.This paper presents a conceptual stakeholder-led engagement methodology, developed from value led business modelling approaches, for determining barriers and facilitators to translational global healthcare research in a country-specific context, in this case the Cambodian prosthetics and orthotics sector.Subsequent research and development work in this area needs to carefully manage and negotiate influencing factors identified through the application of the described methodology, to ensure initiatives (whether research or wider national development work) are sustainable and successful.

Closing the gap in the Janzen-Connell hypothesis: What determines pathogen diversity?

The high tree diversity in tropical forests has long been a puzzle to ecologists. In the 1970s, Janzen and Connell proposed that tree species (hosts) coexist due to the stabilizing actions of specialized enemies. This Janzen-Connell hypothesis was subsequently supported by theoretical studies. Yet, such studies have taken the presence of specialized pathogens for granted, overlooking that pathogen coexistence also requires an explanation. Moreover, stable ecological coexistence does not necessarily imply evolutionary stability. What are the conditions that allow Janzen-Connell effects to evolve? We link theory from community ecology, evolutionary biology and epidemiology to tackle this question, structuring our approach around five theoretical frameworks. Phenomenological Lotka-Volterra competition models provide the most basic framework, which can be restructured to include (single- or multi-)pathogen dynamics. This ecological foundation can be extended to include pathogen evolution. Hosts, of course, may also evolve, and we introduce a coevolutionary model, showing that host-pathogen coevolution can lead to highly diverse systems. Our work unpacks the assumptions underpinning Janzen-Connell and places theoretical bounds on pathogen and host ecology and evolution. The five theoretical frameworks taken together provide a stronger theoretical basis for Janzen-Connell, delivering a wider lens that can yield important insights into the maintenance of diversity in these increasingly threatened systems.

Predicting the impact of COVID-19 non-pharmaceutical intervention on short- and medium-term dynamics of enterovirus D68 in the US.

Recent outbreaks of enterovirus D68 (EV-D68) infections, and their causal linkage with acute flaccid myelitis (AFM), continue to pose a serious public health concern. During 2020 and 2021, the dynamics of EV-D68 and other pathogens have been significantly perturbed by non-pharmaceutical interventions against COVID-19; this perturbation presents a powerful natural experiment for exploring the dynamics of these endemic infections. In this study, we analyzed publicly available data on EV-D68 infections, originally collected through the New Vaccine Surveillance Network, to predict their short- and long-term dynamics following the COVID-19 interventions. Although long-term predictions are sensitive to our assumptions about underlying dynamics and changes in contact rates during the NPI periods, the likelihood of a large outbreak in 2023 appears to be low. Comprehensive surveillance data are needed to accurately characterize future dynamics of EV-D68. The limited incidence of AFM cases in 2022, despite large EV-D68 outbreaks, poses further questions for the timing of the next AFM outbreaks.

Conspecific versus heterospecific transmission shapes host specialization of the phyllosphere microbiome.

In disease ecology, pathogen transmission among conspecific versus heterospecific hosts is known to shape pathogen specialization and virulence, but we do not yet know if similar effects occur at the microbiome level. We tested this idea by experimentally passaging leaf-associated microbiomes either within conspecific or across heterospecific plant hosts. Although conspecific transmission results in persistent host-filtering effects and more within-microbiome network connections, heterospecific transmission results in weaker host-filtering effects but higher levels of interconnectivity. When transplanted onto novel plants, heterospecific lines are less differentiated by host species than conspecific lines, suggesting a shift toward microbiome generalism. Finally, conspecific lines from tomato exhibit a competitive advantage on tomato hosts against those passaged on bean or pepper, suggesting microbiome-level host specialization. Overall, we find that transmission mode and previous host history shape microbiome diversity, with repeated conspecific transmission driving microbiome specialization and repeated heterospecific transmission promoting microbiome generalism.

Relative abundance data can misrepresent heritability of the microbiome.

BACKGROUND: Host genetics can shape microbiome composition, but to what extent it does, remains unclear. Like any other complex trait, this important question can be addressed by estimating the heritability (h2) of the microbiome-the proportion of variance in the abundance in each taxon that is attributable to host genetic variation. However, unlike most complex traits, microbiome heritability is typically based on relative abundance data, where taxon-specific abundances are expressed as the proportion of the total microbial abundance in a sample. RESULTS: We derived an analytical approximation for the heritability that one obtains when using such relative, and not absolute, abundances, based on an underlying quantitative genetic model for absolute abundances. Based on this, we uncovered three problems that can arise when using relative abundances to estimate microbiome heritability: (1) the interdependency between taxa can lead to imprecise heritability estimates. This problem is most apparent for dominant taxa. (2) Large sample size leads to high false discovery rates. With enough statistical power, the result is a strong overestimation of the number of heritable taxa in a community. (3) Microbial co-abundances lead to biased heritability estimates. CONCLUSIONS: We discuss several potential solutions for advancing the field, focusing on technical and statistical developments, and conclude that caution must be taken when interpreting heritability estimates and comparing values across studies. Video Abstract.

The diversity of cGLR receptors: shedding new light on innate immunity.

The characterization of a new group of innate pattern recognition receptors detected in >500 species across the tree of life by Li et al. reveals surprising commonalities and peculiarities shared with other innate receptors. Receptor diversity within and among species opens the way to reconsidering the costs and benefits of innate immune recognition.

Medium-term scenarios of COVID-19 as a function of immune uncertainties and chronic disease.

As the SARS-CoV-2 trajectory continues, the longer-term immuno-epidemiology of COVID-19, the dynamics of Long COVID, and the impact of escape variants are important outstanding questions. We examine these remaining uncertainties with a simple modelling framework that accounts for multiple (antigenic) exposures via infection or vaccination. If immunity (to infection or Long COVID) accumulates rapidly with the valency of exposure, we find that infection levels and the burden of Long COVID are markedly reduced in the medium term. More pessimistic assumptions on host adaptive immune responses illustrate that the longer-term burden of COVID-19 may be elevated for years to come. However, we also find that these outcomes could be mitigated by the eventual introduction of a vaccine eliciting robust (i.e. durable, transmission-blocking and/or 'evolution-proof') immunity. Overall, our work stresses the wide range of future scenarios that still remain, the importance of collecting real-world epidemiological data to identify likely outcomes, and the crucial need for the development of a highly effective transmission-blocking, durable and broadly protective vaccine.

serosim: An R package for simulating serological data arising from vaccination, epidemiological and antibody kinetics processes.

serosim is an open-source R package designed to aid inference from serological studies, by simulating data arising from user-specified vaccine and antibody kinetics processes using a random effects model. Serological data are used to assess population immunity by directly measuring individuals' antibody titers. They uncover locations and/or populations which are susceptible and provide evidence of past infection or vaccination to help inform public health measures and surveillance. Both serological data and new analytical techniques used to interpret them are increasingly widespread. This creates a need for tools to simulate serological studies and the processes underlying observed titer values, as this will enable researchers to identify best practices for serological study design, and provide a standardized framework to evaluate the performance of different inference methods. serosim allows users to specify and adjust model inputs representing underlying processes responsible for generating the observed titer values like time-varying patterns of infection and vaccination, population demography, immunity and antibody kinetics, and serological sampling design in order to best represent the population and disease system(s) of interest. This package will be useful for planning sampling design of future serological studies, understanding determinants of observed serological data, and validating the accuracy and power of new statistical methods.

Mapping the timeliness of routine childhood vaccination in The Gambia: A spatial modelling study.

INTRODUCTION: Timeliness of routine vaccination shapes childhood infection risk and thus is an important public health metric. Estimates of indicators of the timeliness of vaccination are usually produced at the national or regional level, which may conceal epidemiologically relevant local heterogeneities and makeitdifficultto identify pockets of vulnerabilities that could benefit from targeted interventions. Here, we demonstrate the utility of geospatial modelling techniques in generating high-resolution maps of the prevalence of delayed childhood vaccination in The Gambia. To guide local immunisation policy and prioritize key interventions, we also identified the districts with a combination of high estimated prevalence and a significant population of affected infants. METHODS: We used the birth dose of the hepatitis-B vaccine (HepB0), third-dose of the pentavalent vaccine (PENTA3), and the first dose of measles-containing vaccine (MCV1) as examples to map delayed vaccination nationally at a resolution of 1 × 1-km2 pixel. We utilized cluster-level childhood vaccination data from The Gambia 2019-20 Demographic and Health Survey. We adopted a fully Bayesian geostatistical model incorporating publicly available geospatial covariates to aid predictive accuracy. The model was implemented using the integrated nested Laplace approximation-stochastic partial differential equation (INLA-SPDE) approach. RESULTS: We found significant subnational heterogeneity in delayed HepB0, PENTA3 and MCV1 vaccinations. Specificdistricts in the central and eastern regions of The Gambia consistentlyexhibited the highest prevalence of delayed vaccination, while the coastal districts showed alower prevalence forallthree vaccines. We also found that districts in the eastern, central, as well as in coastal parts of The Gambia had a combination of high estimated prevalence of delayed HepB0, PENTA3 and MCV1 and a significant population of affected infants. CONCLUSIONS: Our approach provides decision-makers with a valuable tool to better understand local patterns of untimely childhood vaccination and identify districts where strengthening vaccine delivery systems could have the greatest impact.

Excess mortality associated with the COVID-19 pandemic during the 2020 and 2021 waves in Antananarivo, Madagascar.

INTRODUCTION: COVID-19-associated mortality remains difficult to estimate in sub-Saharan Africa because of the lack of comprehensive systems of death registration. Based on death registers referring to the capital city of Madagascar, we sought to estimate the excess mortality during the COVID-19 pandemic and calculate the loss of life expectancy. METHODS: Death records between 2016 and 2021 were used to estimate weekly excess mortality during the pandemic period. To infer its synchrony with circulation of SARS-CoV-2, a cross-wavelet analysis was performed. Life expectancy loss due to the COVID-19 pandemic was calculated by projecting mortality rates using the Lee and Carter model and extrapolating the prepandemic trends (1990-2019). Differences in life expectancy at birth were disaggregated by cause of death. RESULTS: Peaks of excess mortality in 2020-21 were associated with waves of COVID-19. Estimates of all-cause excess mortality were 38.5 and 64.9 per 100 000 inhabitants in 2020 and 2021, respectively, with excess mortality reaching ≥50% over 6 weeks. In 2021, we quantified a drop of 0.8 and 1.0 years in the life expectancy for men and women, respectively attributable to increased risks of death beyond the age of 60 years. CONCLUSION: We observed high excess mortality during the pandemic period, in particular around the peaks of SARS-CoV-2 circulation in Antananarivo. Our study highlights the need to implement death registration systems in low-income countries to document true toll of a pandemic.

Relative role of community transmission and campus contagion in driving the spread of SARS-CoV-2: Lessons from Princeton University.

Mathematical models have played a crucial role in exploring and guiding pandemic responses. University campuses present a particularly well-documented case for institutional outbreaks, thereby providing a unique opportunity to understand detailed patterns of pathogen spread. Here, we present descriptive and modeling analyses of SARS-CoV-2 transmission on the Princeton University (PU) campus-this model was used throughout the pandemic to inform policy decisions and operational guidelines for the university campus. Epidemic patterns between the university campus and surrounding communities exhibit strong spatiotemporal correlations. Mathematical modeling analysis further suggests that the amount of on-campus transmission was likely limited during much of the wider pandemic until the end of 2021. Finally, we find that a superspreading event likely played a major role in driving the Omicron variant outbreak on the PU campus during the spring semester of the 2021-2022 academic year. Despite large numbers of cases on campus in this period, case levels in surrounding communities remained low, suggesting that there was little spillover transmission from campus to the local community.

Long-term measles antibody profiles following different vaccine schedules in China, a longitudinal study.

Characterizing the long-term kinetics of maternally derived and vaccine-induced measles immunity is critical for informing measles immunization strategies moving forward. Based on two prospective cohorts of children in China, we estimate that maternally derived immunity against measles persists for 2.4 months. Following two-dose series of measles-containing vaccine (MCV) at 8 and 18 months of age, the immune protection against measles is not lifelong, and antibody concentrations are extrapolated to fall below the protective threshold of 200 mIU/ml at 14.3 years. A catch-up MCV dose in addition to the routine doses between 8 months and 5 years reduce the cumulative incidence of seroreversion by 79.3-88.7% by the age of 6 years. Our findings also support a good immune response after the first MCV vaccination at 8 months. These findings, coupled with the effectiveness of a catch-up dose in addition to the routine doses, could be instrumental to relevant stakeholders when planning routine immunization schedules and supplemental immunization activities.

Mechanistic models to meet the challenge of climate change in plant-pathogen systems.

Evidence that climate change will impact the ecology and evolution of individual plant species is growing. However, little, as yet, is known about how climate change will affect interactions between plants and their pathogens. Climate drivers could affect the physiology, and thus demography, and ultimately evolutionary processes affecting both plant hosts and their pathogens. Because the impacts of climate drivers may operate in different directions at different scales of infection, and, furthermore, may be nonlinear, abstracting across these processes may mis-specify outcomes. Here, we use mechanistic models of plant-pathogen interactions to illustrate how counterintuitive outcomes are possible, and we introduce how such framing may contribute to understanding climate effects on plant-pathogen systems. We discuss the evidence-base derived from wild and agricultural plant-pathogen systems that could inform such models, specifically in the direction of estimates of physiological, demographic and evolutionary responses to climate change. We conclude by providing an overview of knowledge gaps and directions for future research in this important area. This article is part of the theme issue 'Infectious disease ecology and evolution in a changing world'.

Long term intrinsic cycling in human life course antibody responses to influenza A(H3N2): an observational and modeling study.

Background: Over a life course, human adaptive immunity to antigenically mutable pathogens exhibits competitive and facilitative interactions. We hypothesize that such interactions may lead to cyclic dynamics in immune responses over a lifetime. Methods: To investigate the cyclic behavior, we analyzed hemagglutination inhibition titers against 21 historical influenza A(H3N2) strains spanning 47 years from a cohort in Guangzhou, China, and applied Fourier spectrum analysis. To investigate possible biological mechanisms, we simulated individual antibody profiles encompassing known feedbacks and interactions due to generally recognized immunological mechanisms. Results: We demonstrated a long-term periodicity (about 24 years) in individual antibody responses. The reported cycles were robust to analytic and sampling approaches. Simulations suggested that individual-level cross-reaction between antigenically similar strains likely explains the reported cycle. We showed that the reported cycles are predictable at both individual and birth cohort level and that cohorts show a diversity of phases of these cycles. Phase of cycle was associated with the risk of seroconversion to circulating strains, after accounting for age and pre-existing titers of the circulating strains. Conclusions: Our findings reveal the existence of long-term periodicities in individual antibody responses to A(H3N2). We hypothesize that these cycles are driven by preexisting antibody responses blunting responses to antigenically similar pathogens (by preventing infection and/or robust antibody responses upon infection), leading to reductions in antigen-specific responses over time until individual's increasing risk leads to an infection with an antigenically distant enough virus to generate a robust immune response. These findings could help disentangle cohort effects from individual-level exposure histories, improve our understanding of observed heterogeneous antibody responses to immunizations, and inform targeted vaccine strategy. Funding: This study was supported by grants from the NIH R56AG048075 (DATC, JL), NIH R01AI114703 (DATC, BY), the Wellcome Trust 200861/Z/16/Z (SR), and 200187/Z/15/Z (SR). This work was also supported by research grants from Guangdong Government HZQB-KCZYZ-2021014 and 2019B121205009 (YG and HZ). DATC, JMR and SR acknowledge support from the National Institutes of Health Fogarty Institute (R01TW0008246). JMR acknowledges support from the Medical Research Council (MR/S004793/1) and the Engineering and Physical Sciences Research Council (EP/N014499/1). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.