Differentiation and adaptation of natural killer cells for anti-malarial immunity.

Natural killer cells employ a diverse arsenal of effector mechanisms to target intracellular pathogens. Differentiation of natural killer (NK) cell activation pathways occurs along a continuum from reliance on innate pro-inflammatory cytokines and stress-induced host ligands through to interaction with signals derived from acquired immune responses. Importantly, the degree of functional differentiation of the NK cell lineage influences the magnitude and specificity of interactions with host cells infected with viruses, bacteria, fungi, and parasites. Individual humans possess a vast diversity of distinct NK cell clones, each with the capacity to vary along this functional differentiation pathway, which - when combined - results in unique individual responses to different infections. Here we summarize these NK cell differentiation events, review evidence for direct interaction of malaria-infected host cells with NK cells and assess how innate inflammatory signals induced by malaria parasite-associated molecular patterns influence the indirect activation and function of NK cells. Finally, we discuss evidence that anti-malarial immunity develops in parallel with advancing NK differentiation, coincident with a loss of reliance on inflammatory signals, and a refined capacity of NK cells to target malaria parasites more precisely, particularly through antibody-dependent mechanisms.

Long-term vaccination strategies to mitigate the impact of SARS-CoV-2 transmission: A modelling study.

BACKGROUND: Vaccines have reduced severe disease and death from Coronavirus Disease 2019 (COVID-19). However, with evidence of waning efficacy coupled with continued evolution of the virus, health programmes need to evaluate the requirement for regular booster doses, considering their impact and cost-effectiveness in the face of ongoing transmission and substantial infection-induced immunity. METHODS AND FINDINGS: We developed a combined immunological-transmission model parameterised with data on transmissibility, severity, and vaccine effectiveness. We simulated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission and vaccine rollout in characteristic global settings with different population age-structures, contact patterns, health system capacities, prior transmission, and vaccine uptake. We quantified the impact of future vaccine booster dose strategies with both ancestral and variant-adapted vaccine products, while considering the potential future emergence of new variants with modified transmission, immune escape, and severity properties. We found that regular boosting of the oldest age group (75+) is an efficient strategy, although large numbers of hospitalisations and deaths could be averted by extending vaccination to younger age groups. In countries with low vaccine coverage and high infection-derived immunity, boosting older at-risk groups was more effective than continuing primary vaccination into younger ages in our model. Our study is limited by uncertainty in key parameters, including the long-term durability of vaccine and infection-induced immunity as well as uncertainty in the future evolution of the virus. CONCLUSIONS: Our modelling suggests that regular boosting of the high-risk population remains an important tool to reduce morbidity and mortality from current and future SARS-CoV-2 variants. Our results suggest that focusing vaccination in the highest-risk cohorts will be the most efficient (and hence cost-effective) strategy to reduce morbidity and mortality.

The genetics of immune and infection phenotypes in wild mice, Mus musculus domesticus.

Wild animals are under constant threat from a wide range of micro- and macroparasites in their environment. Animals make immune responses against parasites, and these are important in affecting the dynamics of parasite populations. Individual animals vary in their anti-parasite immune responses. Genetic polymorphism of immune-related loci contributes to inter-individual differences in immune responses, but most of what we know in this regard comes from studies of humans or laboratory animals; there are very few such studies of wild animals naturally infected with parasites. Here we have investigated the effect of single nucleotide polymorphisms (SNPs) in immune-related loci (the major histocompatibility complex [MHC], and loci coding for cytokines and Toll-like receptors) on a wide range of immune and infection phenotypes in UK wild house mice, Mus musculus domesticus. We found strong associations between SNPs in various MHC and cytokine-coding loci on both immune measures (antibody concentration and cytokine production) and on infection phenotypes (infection with mites, worms and viruses). Our study provides a comprehensive view of how polymorphism of immune-related loci affects immune and infection phenotypes in naturally infected wild rodent populations.

Dry season prevalence of Plasmodium falciparum in asymptomatic gambian children, with a comparative evaluation of diagnostic methods.

BACKGROUND: Subclinical infection with Plasmodium falciparum remains highly prevalent, yet diagnosing these often low-density infections remains a challenge. Infections can be subpatent, falling below the limit of detection for conventional thick-film microscopy and rapid diagnostic testing (RDT). In this study, the prevalence of subclinical P. falciparum infections in school-aged children was characterised at the start of the dry season in the Upper River Region of The Gambia in 2017/2018, with a goal to also compare the utility of different diagnostic tools. METHODS: In a cross-sectional survey of children living in 29 villages on the south bank of the Gambia river (median age of 10 years), matched microscopy, rapid diagnostic test (RDT, detecting histidine-rich protein 2) and polymerase chain reaction (PCR, targeting either 18S rRNA or var gene acidic terminal sequence) were used to determine the prevalence of patent and subpatent infections and to compare the performance of the different diagnostic methods. RESULTS: The prevalence of var gene acidic terminal sequence (varATS) qPCR-detectable infections was 10.2% (141/1381) with a median density of 3.12 parasites/µL. Malaria prevalence was highly heterogeneous across the region, ranging from < 1% to ~ 40% prevalence in different village clusters. Compared to varATS, 18S rRNA PCR detected fewer low-density infections, with an assay sensitivity of 50% and specificity of 98.8%. Parasite prevalence in the cohort was 2.9% by microscopy and 1.5% by RDT. Compared to varATS qPCR, microscopy and RDT had sensitivities of 11.5% and 9.2%, respectively, although both methods were highly specific (> 98%). Samples that were positive by all three tests (varATS qPCR, RDT and microscopy) had significantly higher parasite densities (median = 1705 parasites/µL) than samples that were positive by varATS qPCR only (median = 2.4 parasites/µL). CONCLUSIONS: The majority of subclinical malaria infections in school-aged children were of extremely low parasite density and detectable only by ultra-sensitive PCR analysis. Understanding the duration of these low density infections, their physiological impact and their contribution to sustained parasite transmission is necessary to inform malaria elimination strategies.

Antibody-Dependent Natural Killer Cell Activation After Ebola Vaccination.

BACKGROUND: Antibody Fc-mediated functions, such as antibody-dependent cellular cytotoxicity, contribute to vaccine-induced protection against viral infections. Fc-mediated function of anti-Ebola glycoprotein (GP) antibodies suggest that Fc-dependent activation of effector cells, including natural killer (NK) cells, could play a role in vaccination against Ebola virus disease. METHODS: We analyzed the effect on primary human NK cell activation of anti-Ebola GP antibody in the serum of United Kingdom-based volunteers vaccinated with the novel 2-dose heterologous adenovirus type 26.ZEBOV, modified vaccinia Ankara-BN-Filo vaccine regimen. RESULTS: We demonstrate primary human NK cell CD107a and interferon γ expression, combined with down-regulation of CD16, in response to recombinant Ebola virus GP and post-vaccine dose 1 and dose 2 serum samples. These responses varied significantly with vaccine regimen, and NK cell activation was found to correlate with anti-GP antibody concentration. We also reveal an impact of NK cell differentiation phenotype on antibody-dependent NK cell activation, with highly differentiated CD56dimCD57+ NK cells being the most responsive. CONCLUSIONS: These findings highlight the dual importance of vaccine-induced antibody concentration and NK cell differentiation status in promoting Fc-mediated activation of NK cells after vaccination, raising a potential role for antibody-mediated NK cell activation in vaccine-induced immune responses.

The ecology of immune state in a wild mammal, Mus musculus domesticus.

The immune state of wild animals is largely unknown. Knowing this and what affects it is important in understanding how infection and disease affects wild animals. The immune state of wild animals is also important in understanding the biology of their pathogens, which is directly relevant to explaining pathogen spillover among species, including to humans. The paucity of knowledge about wild animals' immune state is in stark contrast to our exquisitely detailed understanding of the immunobiology of laboratory animals. Making an immune response is costly, and many factors (such as age, sex, infection status, and body condition) have individually been shown to constrain or promote immune responses. But, whether or not these factors affect immune responses and immune state in wild animals, their relative importance, and how they interact (or do not) are unknown. Here, we have investigated the immune ecology of wild house mice-the same species as the laboratory mouse-as an example of a wild mammal, characterising their adaptive humoral, adaptive cellular, and innate immune state. Firstly, we show how immune variation is structured among mouse populations, finding that there can be extensive immune discordance among neighbouring populations. Secondly, we identify the principal factors that underlie the immunological differences among mice, showing that body condition promotes and age constrains individuals' immune state, while factors such as microparasite infection and season are comparatively unimportant. By applying a multifactorial analysis to an immune system-wide analysis, our results bring a new and unified understanding of the immunobiology of a wild mammal.

Influenza Vaccination Primes Human Myeloid Cell Cytokine Secretion and NK Cell Function.

Cytokine-induced memory-like (CIML) NK cells generated in response to proinflammatory cytokines in vitro and in vivo can also be generated by vaccination, exhibiting heightened responses to cytokine stimulation months after their initial induction. Our previous study demonstrated that in vitro human NK cell responses to inactivated influenza virus were also indirectly augmented by very low doses of IL-15, which increased induction of myeloid cell-derived cytokine secretion. These findings led us to hypothesize that IL-15 stimulation could reveal a similar effect for active influenza vaccination and influence CIML NK cell effector functions. In this study, 51 healthy adults were vaccinated with seasonal influenza vaccine, and PBMC were collected before and up to 30 d after vaccination. Myeloid and lymphoid cell cytokine secretion was measured after in vitro PBMC restimulation with low-dose IL-15, alone or in combination with inactivated H3N2 virus; the associated NK cell response was assessed by flow cytometry. PBMC collected 30 d postvaccination showed heightened cytokine production in response to IL-15 compared with PBMC collected at baseline; these responses were further enhanced when IL-15 was combined with H3N2. NK cell activation in response to IL-15 alone (CD25) and H3N2 plus IL-15 (CD25 and IFN-γ) was enhanced postvaccination. We also observed proliferation of less-differentiated NK cells with downregulation of cytokine receptors as early as 3 d after vaccination, suggesting cytokine stimulation in vivo. We conclude that vaccination-induced "training" of accessory cells combines with the generation of CIML NK cells to enhance the overall NK cell response postvaccination.

Novel genetic polymorphisms associated with severe malaria and under selective pressure in North-eastern Tanzania.

Significant selection pressure has been exerted on the genomes of human populations exposed to Plasmodium falciparum infection, resulting in the acquisition of mechanisms of resistance against severe malarial disease. Many host genetic factors, including sickle cell trait, have been associated with reduced risk of developing severe malaria, but do not account for all of the observed phenotypic variation. Identification of novel inherited risk factors relies upon high-resolution genome-wide association studies (GWAS). We present findings of a GWAS of severe malaria performed in a Tanzanian population (n = 914, 15.2 million SNPs). Beyond the expected association with the sickle cell HbS variant, we identify protective associations within two interleukin receptors (IL-23R and IL-12RBR2) and the kelch-like protein KLHL3 (all P<10-6), as well as near significant effects for Major Histocompatibility Complex (MHC) haplotypes. Complementary analyses, based on detecting extended haplotype homozygosity, identified SYNJ2BP, GCLC and MHC as potential loci under recent positive selection. Through whole genome sequencing of an independent Tanzanian cohort (parent-child trios n = 247), we confirm the allele frequencies of common polymorphisms underlying associations and selection, as well as the presence of multiple structural variants that could be in linkage with these SNPs. Imputation of structural variants in a region encompassing the glycophorin genes on chromosome 4, led to the characterisation of more than 50 rare variants, and individually no strong evidence of associations with severe malaria in our primary dataset (P>0.3). Our approach demonstrates the potential of a joint genotyping-sequencing strategy to identify as-yet unknown susceptibility loci in an African population with well-characterised malaria phenotypes. The regions encompassing these loci are potential targets for the design of much needed interventions for preventing or treating malarial disease.

The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis.

BACKGROUND: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. METHODS AND FINDINGS: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. CONCLUSIONS: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.

IL-15 Promotes Polyfunctional NK Cell Responses to Influenza by Boosting IL-12 Production.

IL-15 is a key regulator of NK cell maintenance and proliferation and synergizes with other myeloid cell-derived cytokines to enhance NK cell effector function. At low concentrations, trans-presentation of IL-15 by dendritic cells can activate NK cells, whereas at higher concentrations it can act directly on NK cells, independently of accessory cells. In this study, we investigate the potential for IL-15 to boost responses to influenza virus by promoting accessory cell function. We find that coculture of human PBMCs with inactivated whole influenza virus (A/Victoria/361/2011) in the presence of very low concentrations of IL-15 results in increased production of myeloid cell-derived cytokines, including IL-12, IFN-α2, GM-CSF, and IL-1ß, and an increased frequency of polyfunctional NK cells (defined by the expression of two or more of CD107a, IFN-γ, and CD25). Neutralization experiments demonstrate that IL-15-mediated enhancement of NK cell responses is primarily dependent on IL-12 and partially dependent on IFN-αßR1 signaling. Critically, IL-15 boosted the production of IL-12 in influenza-stimulated blood myeloid dendritic cells. IL-15 costimulation also restored the ability of less-differentiated NK cells from human CMV-seropositive individuals to respond to influenza virus. These data suggest that very low concentrations of IL-15 play an important role in boosting accessory cell function to support NK cell effector functions.

CMV and natural killer cells: shaping the response to vaccination.

Cytomegaloviruses (CMVs) are highly prevalent, persistent human pathogens that not only evade but also shape our immune responses. Natural killer (NK) cells play an important role in the control of CMV and CMVs have in turn developed a plethora of immunoevasion mechanisms targeting NK cells. This complex interplay can leave a long-lasting imprint on the immune system in general and affect responses toward other pathogens and vaccines. This review aims to provide an overview of NK cell biology and development, the manipulation of NK cells by CMVs and the potential impact of these evasion strategies on responses to vaccination.

Enhancement of cytokine-driven NK cell IFN-γ production after vaccination of HCMV infected Africans.

Human cytomegalovirus (HCMV) infection drives the phenotypic and functional differentiation of NK cells, thereby influencing the responses of these cells after vaccination. NK cell functional differentiation is particularly advanced in African populations with universal exposure to HCMV. To investigate the impact of advanced differentiation on vaccine-induced responses, we studied NK-cell function before and after vaccination with Trivalent Influenza Vaccine (TIV) or diphtheria, tetanus, pertussis, inactivated poliovirus vaccine (DTPiP) in Africans with universal, lifelong HCMV exposure. In contrast to populations with lower prevalence of HCMV infection, no significant enhancement of NK-cell responses (IFN-γ, CD107a, CD25) occurred after in vitro re-stimulation of post-vaccination NK cells with TIV or DTPiP antigens compared to pre-vaccination baseline cells. However, both vaccinations resulted in higher frequencies of NK cells producing IFN-γ in response to exogenous IL-12 with IL-18, which persisted for up to 6 months. Enhanced cytokine responsiveness was restricted to less differentiated NK cells, with increased frequencies of IFN-γ+ cells observed within CD56bright CD57- , CD56dim CD57- NKG2C- and CD56dim CD57- NKG2C+ NK-cell subsets. These data suggest a common mechanism whereby different vaccines enhance NK cell IFN-γ function in HCMV infected donors and raise the potential for further exploitation of NK cell "pre-activation" to improve vaccine effectiveness.

Haemolysis and haem oxygenase-1 induction during persistent "asymptomatic" malaria infection in Burkinabé children.

BACKGROUND: The haemolysis associated with clinical episodes of malaria results in the liberation of haem, which activates the enzyme haem oxygenase-1 (HO-1). HO-1 has been shown to reduce neutrophil function and increase susceptibility to invasive bacterial disease. However, the majority of community-associated malaria infections are subclinical, often termed "asymptomatic" and the consequences of low-grade haemolysis during subclinical malaria infection are unknown. STUDY DESIGN AND RESULTS: As part of an ongoing study of subclinical malaria in Burkina Faso, 23 children with subclinical Plasmodium falciparum infections (determined by qPCR) were compared with 21 village-matched uninfected control children. Infected children showed evidence of persistent haemolysis over 35 days, with raised plasma haem and HO-1 concentrations. Concentrations of IL-10, which can also directly activate HO-1, were also higher in infected children compared to uninfected children. Regression analysis revealed that HO-1 was associated with haemolysis, but not with parasite density, anaemia or IL-10 concentration. CONCLUSIONS: This study reveals that subclinical P. falciparum malaria infection is associated with sustained haemolysis and the induction of HO-1. Given the association between HO-1, neutrophil dysfunction and increased risk of Salmonella bacteraemia, prolonged HO-1 induction may explain epidemiological associations and geographic overlap between malaria and invasive bacterial disease. Further studies are needed to understand the consequences of persistent subclinical malaria infection, low-grade haemolysis and raised HO-1 on immune cell function and risk of comorbidities.

Influenza Vaccination Generates Cytokine-Induced Memory-like NK Cells: Impact of Human Cytomegalovirus Infection.

Human NK cells are activated by cytokines, immune complexes, and signals transduced via activating ligands on other host cells. After vaccination, or during secondary infection, adaptive immune responses can enhance both cytokine-driven and Ab-dependent NK cell responses. However, induction of NK cells for enhanced function after in vitro exposure to innate inflammatory cytokines has also been reported and may synergize with adaptive signals to potentiate NK cell activity during infection or vaccination. To test this hypothesis, we examined the effect of seasonal influenza vaccination on NK cell function and phenotype in 52 previously unvaccinated individuals. Enhanced, IL-2-dependent, NK cell IFN-γ responses to Influenza A/California/7/2009 virus were detected up to 4 wk postvaccination and higher in human CMV (HCMV)-seronegative (HCMV(-)) individuals than in HCMV-seropositive (HCMV(+)) individuals. By comparison, robust NK cell degranulation responses were observed both before and after vaccination, due to high titers of naturally occurring anti-influenza Abs in human plasma, and did not differ between HCMV(+) and HCMV(-) subjects. In addition to these IL-2-dependent and Ab-dependent responses, NK cell responses to innate cytokines were also enhanced after influenza vaccination; this was associated with proliferation of CD57(-) NK cells and was most evident in HCMV(+) subjects. Similar enhancement of cytokine responsiveness was observed when NK cells were cocultured in vitro with Influenza A/California/7/2009 virus, and this was at least partially dependent upon IFN-αßR2. In summary, our data indicate that attenuated or live viral vaccines promote cytokine-induced memory-like NK cells and that this process is influenced by HCMV infection.

African glucose-6-phosphate dehydrogenase alleles associated with protection from severe malaria in heterozygous females in Tanzania.

X-linked Glucose-6-phosphate dehydrogenase (G6PD) A- deficiency is prevalent in sub-Saharan Africa populations, and has been associated with protection from severe malaria. Whether females and/or males are protected by G6PD deficiency is uncertain, due in part to G6PD and malaria phenotypic complexity and misclassification. Almost all large association studies have genotyped a limited number of G6PD SNPs (e.g. G6PD202 / G6PD376), and this approach has been too blunt to capture the complete epidemiological picture. Here we have identified 68 G6PD polymorphisms and analysed 29 of these (i.e. those with a minor allele frequency greater than 1%) in 983 severe malaria cases and controls in Tanzania. We establish, across a number of SNPs including G6PD376, that only female heterozygotes are protected from severe malaria. Haplotype analysis reveals the G6PD locus to be under balancing selection, suggesting a mechanism of protection relying on alleles at modest frequency and avoiding fixation, where protection provided by G6PD deficiency against severe malaria is offset by increased risk of life-threatening complications. Our study also demonstrates that the much-needed large-scale studies of severe malaria and G6PD enzymatic function across African populations require the identification and analysis of the full repertoire of G6PD genetic markers.

Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens.

Natural killer (NK) cells have a crucial role in combating infections and cancers and their surface receptors can directly recognize and respond to damaged, transformed or non-self cells. Whereas some virus-infected cells are recognized by this same route, NK-cell responses to many pathogens are triggered by a different mechanism. Activation of NK cells by these pathogens requires the presence of accessory cells such as monocytes, macrophages and dendritic cells. Recent studies have identified numerous pathogen-recognition receptors that enable accessory cells to recognize different pathogens and subsequently transmit signals--both soluble and contact-dependent--to NK cells, which respond by upregulating their cytotoxic potential and the production of inflammatory cytokines.

Malaria Host Candidate Genes Validated by Association With Current, Recent, and Historical Measures of Transmission Intensity.

Background: Human malaria susceptibility is determined by multiple genetic factors. It is unclear, however, which genetic variants remain important over time. Methods: Genetic associations of 175 high-quality polymorphisms within several malaria candidate genes were examined in a sample of 8096 individuals from northeast Tanzania using altitude, seroconversion rates, and parasite rates as proxies of historical, recent, and current malaria transmission intensity. A principal component analysis was used to derive 2 alternative measures of overall malaria propensity of a location across different time scales. Results: Common red blood cell polymorphisms (ie, hemoglobin S, glucose-6-phosphate dehydrogenase, and α-thalassemia) were the only ones to be associated with all 3 measures of transmission intensity and the first principal component. Moderate associations were found between some immune response genes (ie, IL3 and IL13) and parasite rates, but these could not be reproduced using the alternative measures of malaria propensity. Conclusions: We have demonstrated the potential of using altitude and seroconversion rate as measures of malaria transmission capturing medium- to long-term time scales to detect genetic associations that are likely to persist over time. These measures also have the advantage of minimizing the deleterious effects of random factors affecting parasite rates on the respective association signals.

Host Resistance to Plasmodium-Induced Acute Immune Pathology Is Regulated by Interleukin-10 Receptor Signaling.

The resolution of malaria infection is dependent on a balance between proinflammatory and regulatory immune responses. While early effector T cell responses are required for limiting parasitemia, these responses need to be switched off by regulatory mechanisms in a timely manner to avoid immune-mediated tissue damage. Interleukin-10 receptor (IL-10R) signaling is considered to be a vital component of regulatory responses, although its role in host resistance to severe immune pathology during acute malaria infections is not fully understood. In this study, we have determined the contribution of IL-10R signaling to the regulation of immune responses during Plasmodium berghei ANKA-induced experimental cerebral malaria (ECM). We show that antibody-mediated blockade of the IL-10R during P. berghei ANKA infection in ECM-resistant BALB/c mice leads to amplified T cell activation, higher serum gamma interferon (IFN-γ) concentrations, enhanced intravascular accumulation of both parasitized red blood cells and CD8+ T cells to the brain, and an increased incidence of ECM. Importantly, the pathogenic effects of IL-10R blockade during P. berghei ANKA infection were reversible by depletion of T cells and neutralization of IFN-γ. Our findings underscore the importance of IL-10R signaling in preventing T-cell- and cytokine-mediated pathology during potentially lethal malaria infections.

Impaired NK Cell Responses to Pertussis and H1N1 Influenza Vaccine Antigens in Human Cytomegalovirus-Infected Individuals.

NK cells contribute to postvaccination immune responses after activation by IL-2 from Ag-specific memory T cells or by cross-linking of the low-affinity IgG receptor, CD16, by Ag-Ab immune complexes. Sensitivity of NK cells to these signals from the adaptive immune system is heterogeneous and influenced by their stage of differentiation. CD56(dim)CD57(+) NK cells are less responsive to IL-2 and produce less IFN-γ in response to T cell-mediated activation than do CD56(bright) or CD56(dim)CD57(-) NK cells. Conversely, NK cell cytotoxicity, as measured by degranulation, is maintained across the CD56(dim) subsets. Human CMV (HCMV), a highly prevalent herpes virus causing lifelong, usually latent, infections, drives the expansion of the CD56(dim)CD57(+)NKG2C(+) NK cell population, skewing the NK cell repertoire in favor of cytotoxic responses at the expense of cytokine-driven responses. We hypothesized, therefore, that HCMV seropositivity would be associated with altered NK cell responses to vaccine Ags. In a cross-sectional study of 152 U.K. adults, with HCMV seroprevalence rate of 36%, we find that HCMV seropositivity is associated with lower NK cell IFN-γ production and degranulation after in vitro restimulation with pertussis or H1N1 influenza vaccine Ags. Higher expression of CD57/NKG2C and lower expression of IL-18Rα on NK cells from HCMV seropositive subjects do not fully explain these impaired responses, which are likely the result of multiple receptor-ligand interactions. This study demonstrates for the first time, to our knowledge, that HCMV serostatus influences NK cell contributions to adaptive immunity and raises important questions regarding the impact of HCMV infection on vaccine efficacy.

IL-18-induced expression of high-affinity IL-2R on murine NK cells is essential for NK-cell IFN-γ production during murine Plasmodium yoelii infection.

Early production of pro-inflammatory cytokines, including IFN-γ, is essential for control of blood-stage malaria infections. We have shown that IFN-γ production can be induced among human natural killer (NK) cells by coculture with Plasmodium falciparum infected erythrocytes, but the importance of this response is unclear. To further explore the role of NK cells during malaria infection, we have characterized the NK-cell response of C57BL/6 mice during lethal (PyYM) or nonlethal (Py17XNL) P. yoelii infection. Ex vivo flow cytometry revealed that NK cells are activated within 24 h of Py17XNL blood-stage infection, expressing CD25 and producing IFN-γ; this response was blunted and delayed during PyYM infection. CD25 expression and IFN-γ production were highly correlated, suggesting a causal relationship between the two responses. Subsequent in vitro experiments revealed that IL-18 signaling is essential for induction of CD25 and synergizes with IL-12 to enhance CD25 expression on splenic NK cells. In accordance with this, Py17XNL-infected erythrocytes induced NK-cell CD25 expression and IFN-γ production in a manner that is completely IL-18- and partially IL-12-dependent, and IFN-γ production is enhanced by IL-2. These data suggest that IL-2 signaling via CD25 amplifies IL-18- and IL-12-mediated NK-cell activation during malaria infection.