The dynamics and longevity of circulating CD4 + memory T cells depend on cell age and not the chronological age of the host.

Quantifying the kinetics with which memory T cell populations are generated and maintained is essential for identifying the determinants of the duration of immunity. The quality and persistence of circulating CD4 + effector memory (T EM ) and central memory (T CM ) T cells in mice appear to shift with age, but it is unclear whether these changes are driven by the aging host environment, by cell age effects, or both. Here we address these issues by combining DNA labelling methods, established fate-mapping systems, a novel reporter mouse strain, and mathematical models. Together, these allow us to quantify the dynamics of both young and established circulating memory CD4 + T cell subsets, within both young and old mice. We show that that these cells and their descendents become more persistent the longer they reside within the T CM and T EM pools. This behaviour may limit memory CD4 T cell diversity by skewing TCR repertoires towards clones generated early in life, but may also compensate for functional defects in new memory cells generated in old age. Author summary: Our long-term protection against infections depends in part on the maintenance of diverse populations of memory CD4 T cells, which are made in response to the initial exposure to the pathogen or a vaccine. These cells are not long-lived, but instead are maintained dynamically at a clonal level through loss and division. Understanding how immune memory persists therefore requires measuring these rates of these processes, and how they might change with age. Here we combine experiments in mice with mathematical models to show that memory CD4 T cells exhibit complex dynamics but increase their capacity to survive as they age. This dynamic implies that as individuals age, their memory CD4 T cell populations become enriched for older clones. This established memory may compensate for functional defects in new T cell responses generated later in life.

Detection of Novel Influenza Viruses Through Community and Healthcare Testing: Implications for Surveillance Efforts in the United States.

BACKGROUND: Novel influenza viruses pose a potential pandemic risk, and rapid detection of infections in humans is critical to characterizing the virus and facilitating the implementation of public health response measures. METHODS: We use a probabilistic framework to estimate the likelihood that novel influenza virus cases would be detected through testing in different community and healthcare settings (urgent care, emergency department, hospital, and intensive care unit [ICU]) while at low frequencies in the United States. Parameters were informed by data on seasonal influenza virus activity and existing testing practices. RESULTS: In a baseline scenario reflecting the presence of 100 novel virus infections with similar severity to seasonal influenza viruses, the median probability of detecting at least one infection per month was highest in urgent care settings (72%) and when community testing was conducted at random among the general population (77%). However, urgent care testing was over 15 times more efficient (estimated as the number of cases detected per 100,000 tests) due to the larger number of tests required for community testing. In scenarios that assumed increased clinical severity of novel virus infection, median detection probabilities increased across all healthcare settings, particularly in hospitals and ICUs (up to 100%) where testing also became more efficient. CONCLUSIONS: Our results suggest that novel influenza virus circulation is likely to be detected through existing healthcare surveillance, with the most efficient testing setting impacted by the disease severity profile. These analyses can help inform future testing strategies to maximize the likelihood of novel influenza detection.

Effect of Rhodococcus opacus PD630 on selenium phytoremediation by Brassica oleracea.

The purpose of this study was to evaluate the potential of microbial-enhanced Brassica oleracea for the phytoremediation of seleniferous soils. The effect of selenite (Se(IV)) and selenate (Se(VI)) on B. oleracea (1-100 mg.L-1) was examined through germination (7 d) and pot (30 d) trials. Microbial analysis was conducted to verify the toxic effect of various Se concentrations (1-500 mg.L-1) on Rhodococcus opacus PD360, and to determine if it exhibits plant growth promoter traits. R. opacus PD630 was found to tolerate high concentrations of both Se(IV) and Se(VI), above 100 mg.L-1. R. opacus PD630 reduced Se(IV) and Se(VI) over 7 days, with a Se conversion efficiency between 60 and 80%. Germination results indicated lower concentrations (0-10 mg.L-1) of Se(IV) and Se(VI) gave a higher shoot length (> 4 cm). B. oleracea accumulated 600-1,000 mg.kg-1 dry weight (DW) of Se(IV) and Se(VI), making it a secondary accumulator of Se. Moreover, seeds inoculated with R. opacus PD360 showed increased Se uptake (up to 1,200 mg Se.kg-1 DW). In addition, bioconcentration and translocation factors were greater than one. The results indicate a synergistic effect between R. opacus PD630 and B. oleracea for Se phytoextraction from polluted soils.

This article examines how Brassica oleracea may be used to improve seleniferous soils and how Rhodococcus opacus can be added to increase biofortification. The research shows great potential for combining Brassica species with bacterial isolates to remove selenium from heavily contaminated soils.

The role of asymptomatic infections in influenza transmission: what do we really know.

Before the COVID-19 pandemic, the role of asymptomatic influenza virus infections in influenza transmission was uncertain. However, the importance of asymptomatic infection with SARS-CoV-2 for onward transmission of COVID-19 has led experts to question whether the role of asymptomatic influenza virus infections in transmission had been underappreciated. We discuss the existing evidence on the frequency of asymptomatic influenza virus infections, the extent to which they contribute to infection transmission, and remaining knowledge gaps. We propose priority areas for further evaluation, study designs, and case definitions to address existing knowledge gaps.

Modeling the impacts of antiviral prophylaxis strategies in mitigating seasonal influenza outbreaks in nursing homes.

BACKGROUND: Antiviral chemoprophylaxis is recommended for use during influenza outbreaks in nursing homes to prevent transmission and severe disease among non-ill residents. Centers for Disease Control and Prevention (CDC) guidance recommends prophylaxis be initiated for all non-ill residents once an influenza outbreak is detected and be continued for at least 14 days and until seven days after the last laboratory-confirmed influenza case is identified. However, not all facilities strictly adhere to this guidance and the impact of such partial adherence is not fully understood. METHODS: We developed a stochastic compartmental framework to model influenza transmission within an average-sized U.S. nursing home. We compared the number of symptomatic illnesses and hospitalizations under varying prophylaxis implementation strategies, in addition to different levels of prophylaxis uptake and adherence by residents and healthcare personnel (HCP). RESULTS: Prophylaxis implemented according to current guidance reduced total symptomatic illnesses and hospitalizations among residents by an average of 12% and 36%, respectively, compared with no prophylaxis. We did not find evidence that alternative implementations of prophylaxis were more effective: compared to full adoption of current guidance, partial adoption resulted in increased symptomatic illnesses and/or hospitalizations, and longer or earlier adoption offered no additional improvements. In addition, increasing uptake and adherence among nursing home residents was effective in reducing resident illnesses and hospitalizations, but increasing HCP uptake had minimal indirect impacts for residents. CONCLUSIONS: The greatest benefits of influenza prophylaxis during nursing home outbreaks will likely be achieved through increasing uptake and adherence among residents and following current CDC guidance.

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.

Evaluating Potential Impacts of a Preferential Vaccine Recommendation for Adults 65 Years of Age and Older on US Influenza Burden.

BACKGROUND: High-dose, adjuvanted, and recombinant influenza vaccines may offer improved effectiveness among older adults compared with standard-dose, unadjuvanted, inactivated vaccines. However, the Advisory Committee on Immunization Practices (ACIP) only recently recommended preferential use of these "higher-dose or adjuvanted" vaccines. One concern was that individuals might delay or decline vaccination if a preferred vaccine is not readily available. METHODS: We mathematically model how a recommendation for preferential use of higher-dose or adjuvanted vaccines in adults ≥65 years might impact influenza burden in the United States during exemplar "high-" and "low-"severity seasons. We assume higher-dose or adjuvanted vaccines are more effective than standard vaccines and that such a recommendation would increase uptake of the former but could cause (i) delays in administration of additional higher-dose or adjuvanted vaccines relative to standard vaccines and/or (ii) reductions in overall coverage if individuals only offered standard vaccines forego vaccination. RESULTS: In a best-case scenario, assuming no delay or coverage reduction, a new recommendation could decrease hospitalizations and deaths in adults ≥65 years by 0%-4% compared with current uptake. However, intermediate and worst-case scenarios, with assumed delays of 3 or 6 weeks and/or 10% or 20% reductions in coverage, included projections in which hospitalizations and deaths increased by over 7%. CONCLUSIONS: We estimate that increased use of higher-dose or adjuvanted vaccines could decrease influenza burden in adults ≥65 in the United States provided there is timely and adequate access to these vaccines, and that standard vaccines are administered when they are unavailable.

Healthy dynamics of CD4 T cells may drive HIV resurgence in perinatally-infected infants on antiretroviral therapy.

In 2019 there were 490,000 children under five living with HIV. Understanding the dynamics of HIV suppression and rebound in this age group is crucial to optimizing treatment strategies and increasing the likelihood of infants achieving and sustaining viral suppression. Here we studied data from a cohort of 122 perinatally-infected infants who initiated antiretroviral treatment (ART) early after birth and were followed for up to four years. These data included longitudinal measurements of viral load (VL) and CD4 T cell numbers, together with information regarding treatment adherence. We previously showed that the dynamics of HIV decline in 53 of these infants who suppressed VL within one year were similar to those in adults. However, in extending our analysis to all 122 infants, we find that a deterministic model of HIV infection in adults cannot explain the full diversity in infant trajectories. We therefore adapt this model to include imperfect ART adherence and natural CD4 T cell decline and reconstitution processes in infants. We find that individual variation in both processes must be included to obtain the best fits. We also find that infants with faster rates of CD4 reconstitution on ART were more likely to experience resurgences in VL. Overall, our findings highlight the importance of combining mathematical modeling with clinical data to disentangle the role of natural immune processes and viral dynamics during HIV infection.

The Optimisation of Cooking Parameters for Spirt Whiskey Production from Native Irish Wheat: A Response Surface Method Approach.

Barley and maize have dominated the Irish whiskey sector, but in recent years, alternative grains have started to gain traction. Ireland has a high average wheat yield, producing grain that is high in starch but low in protein, offering the potential for use in distillation. To successfully utilise Irish-grown wheat in distillation, cultivars that are suitable to the Irish climate and give high yields of alcohol need to be identified. This necessitates the development of a rapid screening test for grain alcohol yield. This study examined the optimal temperature, time period, α-amylase dose rate, and calcium concentration to be used in the cooking of wheat grain to maximise alcohol yields. It was determined that lower cooking temperatures are more successful in achieving higher alcohol yields, and it was confirmed that temperature is a key variable in the cooking process. By optimising all parameters, alcohol yields of 458 LA/tonne were obtained, demonstrating that the optimum parameters can be successfully used for both hard and soft endoderm wheat produced in Ireland as well as for different varieties. This indicates potential for producing higher alcohol yields using Irish-grown wheat in Irish distilleries.

Response Surface Methods to Optimise Milling Parameters for Spirit Alcohol Production from Irish Wheat Grain.

To standardise research activity and determine alcohol yield from native Irish hard wheat grain, a benchmark approach that reflects Irish industry norms is required. The goal of this study was to optimise milling parameters, grain particle size, and grain to liquid ratio towards developing a standard process. Hard wheat (Triticum avestivum cv. Costello) was used in this study. Experiments utilised a response surface method approach. When both 30 and 35 g of flour were used at a particle size of 0.2 mm, alcohol yield was >350 L of alcohol per tonne of grain (LA/tonne), but with a particle size of 0.65 and 1.1 mm, alcohol yield decreased to between 250 and 300 LA/tonne. It was noted that, during response surface study, >300 LA/tonne was achieved when grain amounts were >25 g, at a particle size of 0.2 mm; therefore, a follow-up experiment was conducted to determine whether there was a significant difference in grain amounts ranging from 25 to 35 g. During this experiment, no significant difference in alcohol yield was observed between 30 and 35 g of grain. Because there were no significant differences, the ideal milling parameters for alcohol yield were determined to be 30 g of flour with a particle size of 0.2 mm, achieving 389.5 LA/tonne. This study concludes that hard wheat can successfully be used for alcohol production, achieving >380 LA/tonne, when a milling size of 0.2 mm and more than 30 g of grain are used, and as such presents an opportunity for its increased use in Irish distilleries.

Vaccine nationalism and the dynamics and control of SARS-CoV-2.

Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to exert globally, yet vaccine distribution remains unequal among countries. To examine the potential epidemiological and evolutionary impacts of "vaccine nationalism," we extend previous models to include simple scenarios of stockpiling between two regions. In general, when vaccines are widely available and the immunity they confer is robust, sharing doses minimizes total cases across regions. A number of subtleties arise when the populations and transmission rates in each region differ, depending on evolutionary assumptions and vaccine availability. When the waning of natural immunity contributes most to evolutionary potential, sustained transmission in low-access regions results in an increased potential for antigenic evolution, which may result in the emergence of novel variants that affect epidemiological characteristics globally. Overall, our results stress the importance of rapid, equitable vaccine distribution for global control of the pandemic.

Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19.

Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.

Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes.

Given vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two critical issues arise: How timing of delivery of the second dose will affect infection dynamics and how it will affect prospects for the evolution of viral immune escape via a buildup of partially immune individuals. Both hinge on the robustness of the immune response elicited by a single dose as compared with natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short term, focusing on one dose generally decreases infections, but that longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection and find that a one-dose policy may increase the potential for antigenic evolution under certain conditions of partial population immunity. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose and to ramp up vaccination efforts globally.

Epidemiological and evolutionary considerations of SARS-CoV-2 vaccine dosing regimes.

As the threat of Covid-19 continues and in the face of vaccine dose shortages and logistical challenges, various deployment strategies are being proposed to increase population immunity levels. How timing of delivery of the second dose affects infection burden but also prospects for the evolution of viral immune escape are critical questions. Both hinge on the strength and duration (i.e. robustness) of the immune response elicited by a single dose, compared to natural and two-dose immunity. Building on an existing immuno-epidemiological model, we find that in the short-term, focusing on one dose generally decreases infections, but longer-term outcomes depend on this relative immune robustness. We then explore three scenarios of selection, evaluating how different second dose delays might drive immune escape via a build-up of partially immune individuals. Under certain scenarios, we find that a one-dose policy may increase the potential for antigenic evolution. We highlight the critical need to test viral loads and quantify immune responses after one vaccine dose, and to ramp up vaccination efforts throughout the world.

Analysis of respiratory and systemic immune responses in COVID-19 reveals mechanisms of disease pathogenesis.

Immune responses to respiratory viruses like SARS-CoV-2 originate and function in the lung, yet assessments of human immunity are often limited to blood. Here, we conducted longitudinal, high-dimensional profiling of paired airway and blood samples from patients with severe COVID-19, revealing immune processes in the respiratory tract linked to disease pathogenesis. Survival from severe disease was associated with increased CD4 + T cells and decreased monocyte/macrophage frequencies in the airway, but not in blood. Airway T cells and macrophages exhibited tissue-resident phenotypes and activation signatures, including high level expression and secretion of monocyte chemoattractants CCL2 and CCL3 by airway macrophages. By contrast, monocytes in blood expressed the CCL2-receptor CCR2 and aberrant CD163 + and immature phenotypes. Extensive accumulation of CD163 + monocyte/macrophages within alveolar spaces in COVID-19 lung autopsies suggested recruitment from circulation. Our findings provide evidence that COVID-19 pathogenesis is driven by respiratory immunity, and rationale for site-specific treatment and prevention strategies.

Immune life history, vaccination, and the dynamics of SARS-CoV-2 over the next 5 years.

The future trajectory of the coronavirus disease 2019 (COVID-19) pandemic hinges on the dynamics of adaptive immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, salient features of the immune response elicited by natural infection or vaccination are still uncertain. We use simple epidemiological models to explore estimates for the magnitude and timing of future COVID-19 cases, given different assumptions regarding the protective efficacy and duration of the adaptive immune response to SARS-CoV-2, as well as its interaction with vaccines and nonpharmaceutical interventions. We find that variations in the immune response to primary SARS-CoV-2 infections and a potential vaccine can lead to markedly different immune landscapes and burdens of critically severe cases, ranging from sustained epidemics to near elimination. Our findings illustrate likely complexities in future COVID-19 dynamics and highlight the importance of immunological characterization beyond the measurement of active infections for adequately projecting the immune landscape generated by SARS-CoV-2 infections.

Quantifying the Dynamics of HIV Decline in Perinatally Infected Neonates on Antiretroviral Therapy.

BACKGROUND: Mathematical modeling has provided important insights into HIV infection dynamics in adults undergoing antiretroviral treatment (ART). However, much less is known about the corresponding dynamics in perinatally infected neonates initiating early ART. SETTING: From 2014 to 2017, HIV viral load (VL) was monitored in 122 perinatally infected infants identified at birth and initiating ART within a median of 2 days. Pretreatment infant and maternal covariates, including CD4 T cell counts and percentages, were also measured. METHODS: From the initial cohort, 53 infants demonstrated consistent decline and suppressed VL below the detection threshold (20 copies mL) within 1 year. For 43 of these infants with sufficient VL data, we fit a mathematical model describing the loss of short-lived and long-lived infected cells during ART. We then estimated the lifespans of infected cells and the time to viral suppression, and tested for correlations with pretreatment covariates. RESULTS: Most parameters governing the kinetics of VL decline were consistent with those obtained previously from adults and other infants. However, our estimates of the lifespan of short-lived infected cells were longer than published values. This difference may reflect sparse sampling during the early stages of VL decline, when the loss of short-lived cells is most apparent. In addition, infants with higher pretreatment CD4 percentage or lower pretreatment VL trended toward more rapid viral suppression. CONCLUSIONS: HIV dynamics in perinatally infected neonates initiating early ART are broadly similar to those observed in other age groups. Accelerated viral suppression is also associated with higher CD4 percentage and lower VL.

ushr: Understanding suppression of HIV in R.

BACKGROUND: HIV/AIDS is responsible for the deaths of one million people every year. Although mathematical modeling has provided many insights into the dynamics of HIV infection, there is still a lack of accessible tools for researchers unfamiliar with modeling techniques to apply them to their own clinical data. RESULTS: Here we present ushr, a free and open-source R package that models the decline of HIV during antiretroviral treatment (ART) using a popular mathematical framework. ushr can be applied to longitudinal data of viral load measurements, and provides processing tools to prepare it for computational analysis. By mathematically fitting the data, important biological parameters can then be estimated, including the lifespans of short and long-lived infected cells, and the time to reach viral suppression below a defined detection threshold. The package also provides visualization and summary tools for fast assessment of model results. CONCLUSIONS: ushr enables researchers without a strong mathematical or computational background to model the dynamics of HIV using longitudinal clinical data. Increasing accessibility to such methods may facilitate quantitative analysis across a broader range of independent studies, so that greater insights on HIV infection and treatment dynamics may be gained.

Tissue-Resident Memory T Cells in Mice and Humans: Towards a Quantitative Ecology.

In recent years, tissue-resident memory T cells (TRM) have emerged as essential components of immunological memory. Following antigenic challenge, TRM remain in nonlymphoid tissues and defend against re-exposure. Although accumulating evidence suggests important roles for TRM in mediating protective immunity, fundamental aspects of the population biology of TRM remain poorly understood. In this article, we discuss how results from different systems shed light on the ecological dynamics of TRM in mice and humans. We highlight the importance of dissecting processes contributing to TRM maintenance, and how these might vary across phenotypically and spatially heterogeneous subsets. We also discuss how the diversity of TRM communities within specific tissues may evolve under competition and in response to antigenic perturbation. Throughout, we illustrate how mathematical models can clarify inferences obtained from experimental data and help elucidate the homeostatic mechanisms underpinning the ecology of TRM populations.