Behavioral differences among domestic cats in the response to cat-attracting plants and their volatile compounds reveal a potential distinct mechanism of action for actinidine.

BACKGROUND: It has been known for centuries that cats respond euphorically to Nepeta cataria (catnip). Recently, we have shown that Lonicera tatarica (Tatarian honeysuckle), Actinidia polygama (silver vine), and Valeriana officinalis (valerian) can also elicit this "catnip response". The aim of this study was to learn if the behavior seen in response to these plants is similar to the response to catnip. Furthermore, we studied if these responses are fixed or if there are differences between cats. While nepetalactone was identified decades ago as the molecule responsible for the "catnip response", we know that this volatile is found almost exclusively in catnip. Therefore, we also aimed to identify other compounds in these alternative plants that can elicit the blissful behavior in cats. Bioassays with 6 cats were performed in a low-stress environment, where 5 plants and 13 single compounds were each tested for at least 100 and 17 h, respectively. All responses were video recorded and BORIS software was used to analyze the cats' behavior. RESULTS: Both response duration and behavior differed significantly between the cats. While individual cats had preferences for particular plants, the behavior of individual cats was consistent among all plants. About half a dozen lactones similar in structure to nepetalactone were able to elicit the "catnip response", as were the structurally more distinct molecules actinidine and dihydroactinidiolide. Most cats did not respond to actinidine, whereas those who did, responded longer to this volatile than any of the other secondary plant metabolites, and different behavior was observed. Interestingly, dihydroactinidiolide was also found in excretions and secretions of the red fox, making this the first report of a compound produced by a mammal that can elicit the "catnip response". A range of different cat-attracting compounds was detected by chemical analysis of plant materials but differences in cat behavior could not be directly related to differences in chemical composition of the plants. Together with results of, among others, habituation / dishabituation experiments, this indicates that additional cat-attracting compounds may be present in the plant materials that remain to be discovered. CONCLUSIONS: Collectively, these findings suggest that both the personality of the cat and genetic variation in the genes encoding olfactory receptors may play a role in how cats respond to cat-attracting plants. Furthermore, the data suggest a potential distinct mechanism of action for actinidine.

Biochemical and Histological Insights into the Interaction Between the Canker Pathogen Neofusicoccum parvum and Prunus dulcis.

The number of reports associated with wood dieback caused by fungi in the Botryosphaeriaceae in numerous perennial crops worldwide has significantly increased in the past years. In this study, we investigated the interactions between the canker pathogen Neofusicoccum parvum and the almond tree host (Prunus dulcis), with an emphasis on varietal resistance and host response at the cell wall biochemical and histological levels. Plant bioassays in a shaded house showed that among the four commonly planted commercial almond cultivars ('Butte', 'Carmel', 'Monterey', and 'Nonpareil'), there was no significant varietal difference with respect to resistance to the pathogen. Gummosis was triggered only by fungal infection, not by wounding. A two-dimensional nuclear magnetic resonance and liquid chromatography determination of cell wall polymers showed that infected almond trees differed significantly in their glycosyl and lignin composition compared with healthy, noninfected trees. Response to fungal infection involved a significant increase in lignin, a decrease in glucans, and an overall enrichment in other carbohydrates with a profile similar to those observed in gums. Histological observations revealed the presence of guaiacyl-rich cell wall reinforcements. Confocal microscopy suggested that N. parvum colonized mainly the lumina of xylem vessels and parenchyma cells, and to a lesser extent the gum ducts. We discuss the relevance of these findings in the context of the compartmentalization of decay in trees model in almond and its potential involvement in the vulnerability of the host toward fungal wood canker diseases.

Longitudinal analysis of FcRL5 expression and clonal relationships among classical and atypical memory B cells following malaria.

BACKGROUND: Chronic and frequently recurring infectious diseases, such as malaria, are associated with expanded populations of atypical memory B cells (MBCs). These cells are different from classical MBCs by the lack of surface markers CD21 and CD27 and increased expression of inhibitory receptors, such as FcRL5. While the phenotype and conditions leading to neogenesis of atypical MBCs in malaria-experienced individuals have been studied extensively, the origin of these cells remains equivocal. Functional similarities between FcRL5+ atypical MBCs and FcRL5+ classical MBCs have been reported, suggesting that these cells may be developmentally related. METHODS: Here, a longitudinal analysis of FcRL5 expression in various B cell subsets was performed in two children from a high transmission region in Uganda over a 6-month period in which both children experienced a malaria episode. Using B-cell receptor (BCR)-sequencing to track clonally related cells, the connections between IgM+ and IgG+ atypical MBCs and other B cell subsets were studied. RESULTS: The highest expression of FcRL5 was found among IgG+ atypical MBCs, but FcRL5+ cells were present in all MBC subsets. Following malaria, FcRL5 expression increased in all IgM+ MBC subsets analysed here: classical, activated, and atypical MBCs, while results for IgG+ MBC subsets were inconclusive. IgM+ atypical MBCs showed few connections with other B cell subsets, higher turnover than IgG+ atypical MBCs, and were predominantly derived from naïve B cells and FcRL5- IgM+ classical MBCs. In contrast, IgG+ atypical MBCs were clonally expanded and connected with classical MBCs. IgG+ atypical MBCs present after a malaria episode mainly originated from FcRL5+ IgG+ classical MBCs. CONCLUSIONS: Collectively, these results suggest fundamental differences between unswitched and class-switched B cell populations and provide clues about the primary developmental pathways of atypical MBCs in malaria-experienced individuals.

Three-dimensional modeling of the P. falciparum genome during the erythrocytic cycle reveals a strong connection between genome architecture and gene expression.

The development of the human malaria parasite Plasmodium falciparum is controlled by coordinated changes in gene expression throughout its complex life cycle, but the corresponding regulatory mechanisms are incompletely understood. To study the relationship between genome architecture and gene regulation in Plasmodium, we assayed the genome architecture of P. falciparum at three time points during its erythrocytic (asexual) cycle. Using chromosome conformation capture coupled with next-generation sequencing technology (Hi-C), we obtained high-resolution chromosomal contact maps, which we then used to construct a consensus three-dimensional genome structure for each time point. We observed strong clustering of centromeres, telomeres, ribosomal DNA, and virulence genes, resulting in a complex architecture that cannot be explained by a simple volume exclusion model. Internal virulence gene clusters exhibit domain-like structures in contact maps, suggesting that they play an important role in the genome architecture. Midway during the erythrocytic cycle, at the highly transcriptionally active trophozoite stage, the genome adopts a more open chromatin structure with increased chromosomal intermingling. In addition, we observed reduced expression of genes located in spatial proximity to the repressive subtelomeric center, and colocalization of distinct groups of parasite-specific genes with coordinated expression profiles. Overall, our results are indicative of a strong association between the P. falciparum spatial genome organization and gene expression. Understanding the molecular processes involved in genome conformation dynamics could contribute to the discovery of novel antimalarial strategies.

Responsiveness of cats (Felidae) to silver vine (Actinidia polygama), Tatarian honeysuckle (Lonicera tatarica), valerian (Valeriana officinalis) and catnip (Nepeta cataria).

BACKGROUND: Olfactory stimulation is an often overlooked method of environmental enrichment for cats in captivity. The best known example of olfactory enrichment is the use of catnip, a plant that can cause an apparently euphoric reaction in domestic cats and most of the Pantherinae. It has long been known that some domestic cats and most tigers do not respond to catnip. Although many anecdotes exist of other plants with similar effects, data are lacking about the number of cats that respond to these plants, and if cats that do not respond to catnip respond to any of them. Furthermore, much is still unknown about which chemicals in these plants cause this response. METHODS: We tested catnip, silver vine, Tatarian honeysuckle and valerian root on 100 domestic cats and observed their response. Each cat was offered all four plant materials and a control, multiple times. Catnip and silver vine also were offered to nine tigers. The plant materials were analyzed by gas chromatography coupled with mass spectrometry to quantify concentrations of compounds believed to exert stimulating effects on cats. RESULTS: Nearly all domestic cats responded positively to olfactory enrichment. In agreement with previous studies, one out of every three cats did not respond to catnip. Almost 80% of the domestic cats responded to silver vine and about 50% to Tatarian honeysuckle and valerian root. Although cats predominantly responded to fruit galls of the silver vine plant, some also responded positively to its wood. Of the cats that did not respond to catnip, almost 75% did respond to silver vine and about one out of three to Tatarian honeysuckle. Unlike domestic cats, tigers were either not interested in silver vine or responded disapprovingly. The amount of nepetalactone was highest in catnip and only present at marginal levels in the other plants. Silver vine contained the highest concentrations of all other compounds tested. CONCLUSIONS: Olfactory enrichment for cats may have great potential. Silver vine powder from dried fruit galls and catnip were most popular among domestic cats. Silver vine and Tatarian honeysuckle appear to be good alternatives to catnip for domestic cats that do not respond to catnip.

A Method to Detect and Quantify Eutypa lata and Diplodia seriata-Complex DNA in Grapevine Pruning Wounds.

Trunk diseases are factors that limit sustainability of vineyards worldwide. Botryosphaeria and Eutypa diebacks are caused by several fungi belonging to the Botryosphaeriaceae and Diatrypaceae, respectively, with Diplodia seriata and Eutypa lata being two of the most common species. Previous information indicated that the traditional isolation method used to detect these pathogens from plant samples could underestimate their incidence levels. In the present study, we designed two sets of primers that target the ß-tubulin gene and that are amenable for quantitative real-time PCR (qPCR) Sybr-Green assays for the detection and quantification of D. seriata-complex (DseCQF/R) and E. lata (ElQF/R) DNA. The design of a species-specific assay was achieved for E. lata. For D. seriata, a species-specific assay could not be designed. The low interspecific diversity across ß-tubulin genes resulted in an assay that could not discriminate D. seriata from some closely related species either not yet reported or presenting a low prevalence on grapevine, such as D. intermedia. We validated our technique on grapevine spur samples naturally and artificially infected with D. seriata and E. lata during the dormant season. Experimental grapevines were located in two counties of northern California where the incidence of both pathogens was previously reported. The qPCR assays revealed that a high frequency of pruning wound infections (65%) was achieved naturally by E. lata, while low infection frequency (less than 5%) was observed using the reisolation method. For D. seriata-complex, low (5%) to no natural infection frequencies were observed by the qPCR and the reisolation method, respectively. These results also provided evidence that our qPCR detection methods were more sensitive to assess the incidence of E. lata and D. seriata-complex in plant samples, than traditional isolation techniques. Benefits of molecular methods for the detection of canker pathogens in the field under natural conditions are discussed.

Lysine supplementation is not effective for the prevention or treatment of feline herpesvirus 1 infection in cats: a systematic review.

BACKGROUND: Feline herpesvirus 1 is a highly contagious virus that affects many cats. Virus infection presents with flu-like signs and irritation of ocular and nasal regions. While cats can recover from active infections without medical treatment, examination by a veterinarian is recommended. Lysine supplementation appears to be a popular intervention (recommended by > 90 % of veterinarians in cat hospitals). We investigated the scientific merit of lysine supplementation by systematically reviewing all relevant literature. METHODS: NCBI's PubMed database was used to search for published work on lysine and feline herpesvirus 1, as well as lysine and human herpesvirus 1. Seven studies on lysine and feline herpesvirus 1 (two in vitro studies and 5 studies with cats), and 10 publications on lysine and human herpesvirus 1 (three in vitro studies and 7 clinical trials) were included for qualitative analysis. RESULTS: There is evidence at multiple levels that lysine supplementation is not effective for the prevention or treatment of feline herpesvirus 1 infection in cats. Lysine does not have any antiviral properties, but is believed to act by lowering arginine levels. However, lysine does not antagonize arginine in cats, and evidence that low intracellular arginine concentrations would inhibit viral replication is lacking. Furthermore, lowering arginine levels is highly undesirable since cats cannot synthesize this amino acid themselves. Arginine deficiency will result in hyperammonemia, which may be fatal. In vitro studies with feline herpesvirus 1 showed that lysine has no effect on the replication kinetics of the virus. Finally, and most importantly, several clinical studies with cats have shown that lysine is not effective for the prevention or the treatment of feline herpesvirus 1 infection, and some even reported increased infection frequency and disease severity in cats receiving lysine supplementation. CONCLUSION: We recommend an immediate stop of lysine supplementation because of the complete lack of any scientific evidence for its efficacy.

Differences in phenotype between long-lived memory B cells against Plasmodium falciparum merozoite antigens and variant surface antigens.

Plasmodium falciparum infections elicit strong humoral immune responses to two main groups of antigens expressed by blood-stage parasites: merozoite antigens that are involved in the erythrocyte invasion process and variant surface antigens that mediate endothelial sequestration of infected erythrocytes. Long-lived B cells against both antigen classes can be detected in the circulation for years after exposure, but have not been directly compared. Here, we studied the phenotype of long-lived memory and atypical B cells to merozoite antigens (MSP1 and AMA1) and variant surface antigens (the CIDRα1 domain of PfEMP1) in Ugandan adults before and after local reduction of P. falciparum transmission. After a median of 1.7 years without P. falciparum infections, the percentage of antigen-specific activated B cells declined, but long-lived antigen-specific B cells were still detectable in all individuals. The majority of MSP1/AMA1-specific B cells were CD95+CD11c+ memory B cells, which are primed for rapid differentiation into antibody-secreting cells, and FcRL5-T-bet- atypical B cells. On the other hand, most CIDRα1-specific B cells were CD95-CD11c- memory B cells. CIDRα1-specific B cells were also enriched among a subset of atypical B cells that seem poised for antigen presentation. These results point to differences in how these antigens are recognized or processed by the immune system and how P. falciparum-specific B cells will respond upon re-infection.

MALARIA-WHY DO MOSTLY CHILDREN GET SICK?

Did you know that micro-organisms can live in blood? Plasmodium parasites can infect red blood cells and cause a serious disease called malaria. This disease is mostly seen in young children living in Africa. Sick children have a fever, aches, can feel very tired, and in bad cases, they can even die from malaria. There are medicines that cure malaria, but it is hard to get these to everyone who needs them. Fortunately, as children grow older, they do not feel as sick when they are infected by the malaria-causing parasite. Better yet, adults hardly ever get malaria. The reason for this difference between children and adults has to do with how well the body's defense system can fight off the parasite. Keep reading if you want to learn more about malaria, the Plasmodium parasite and how the immune system fights against it.

Broadly inhibitory antibodies against severe malaria virulence proteins.

Plasmodium falciparum pathology is driven by the accumulation of parasite-infected erythrocytes in microvessels. This process is mediated by the parasite's polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. A subset of PfEMP1 variants that bind human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here, we describe two broadly reactive and binding-inhibitory human monoclonal antibodies against CIDRα1. The antibodies isolated from two different individuals exhibited a similar and consistent EPCR-binding inhibition of 34 CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins as well as parasite sequestration in bioengineered 3D brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with two different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies likely represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.

Histone modification analysis reveals common regulators of gene expression in liver and blood stage merozoites of Plasmodium parasites.

Gene expression in malaria parasites is subject to various layers of regulation, including histone post-translational modifications (PTMs). Gene regulatory mechanisms have been extensively studied during the main developmental stages of Plasmodium parasites inside erythrocytes, from the ring stage following invasion to the schizont stage leading up to egress. However, gene regulation in merozoites that mediate the transition from one host cell to the next is an understudied area of parasite biology. Here, we sought to characterize gene expression and the corresponding histone PTM landscape during this stage of the parasite lifecycle through RNA-seq and ChIP-seq on P. falciparum blood stage schizonts, merozoites, and rings, as well as P. berghei liver stage merozoites. In both hepatic and erythrocytic merozoites, we identified a subset of genes with a unique histone PTM profile characterized by a region of H3K4me3 depletion in their promoter. These genes were upregulated in hepatic and erythrocytic merozoites and rings, had roles in protein export, translation, and host cell remodeling, and shared a DNA motif. These results indicate that similar regulatory mechanisms may underlie merozoite formation in the liver and blood stages. We also observed that H3K4me2 was deposited in gene bodies of gene families encoding variant surface antigens in erythrocytic merozoites, which may facilitate switching of gene expression between different members of these families. Finally, H3K18me and H2K27me were uncoupled from gene expression and were enriched around the centromeres in erythrocytic schizonts and merozoites, suggesting potential roles in the maintenance of chromosomal organization during schizogony. Together, our results demonstrate that extensive changes in gene expression and histone landscape occur during the schizont-to-ring transition to facilitate productive erythrocyte infection. The dynamic remodeling of the transcriptional program in hepatic and erythrocytic merozoites makes this stage attractive as a target for novel anti-malarial drugs that may have activity against both the liver and blood stages.

Atypical B cells consist of subsets with distinct functional profiles.

Atypical B cells are a population of activated B cells that are commonly enriched in individuals with chronic immune activation but are also part of a normal immune response to infection or vaccination. To better define the role of atypical B cells in the human adaptive immune response, we performed single-cell sequencing of transcriptomes, cell surface markers, and B cell receptors in individuals with chronic exposure to the malaria parasite Plasmodium falciparum, a condition known to lead to accumulation of circulating atypical B cells. We identified three previously uncharacterized populations of atypical B cells with distinct transcriptional and functional profiles and observed marked differences among these three subsets in their ability to produce immunoglobulin G upon T-cell-dependent activation. Our findings help explain the conflicting observations in prior studies regarding the function of atypical B cells and highlight their different roles in the adaptive immune response in chronic inflammatory conditions.

A Molecular Analysis of Memory B Cell and Antibody Responses Against Plasmodium falciparum Merozoite Surface Protein 1 in Children and Adults From Uganda.

Memory B cells (MBCs) and plasma antibodies against Plasmodium falciparum (Pf) merozoite antigens are important components of the protective immune response against malaria. To gain understanding of how responses against Pf develop in these two arms of the humoral immune system, we evaluated MBC and antibody responses against the most abundant merozoite antigen, full-length Pf merozoite surface protein 1 (PfMSP1FL), in individuals from a region in Uganda with high Pf transmission. Our results showed that PfMSP1FL-specific B cells in adults with immunological protection against malaria were predominantly IgG+ classical MBCs, while children with incomplete protection mainly harbored IgM+ PfMSP1FL-specific classical MBCs. In contrast, anti-PfMSP1FL plasma IgM reactivity was minimal in both children and adults. Instead, both groups showed high plasma IgG reactivity against PfMSP1FL, with broadening of the response against non-3D7 strains in adults. The B cell receptors encoded by PfMSP1FL-specific IgG+ MBCs carried high levels of amino acid substitutions and recognized relatively conserved epitopes on the highly variable PfMSP1 protein. Proteomics analysis of PfMSP119-specific IgG in plasma of an adult revealed a limited repertoire of anti-MSP1 antibodies, most of which were IgG1 or IgG3. Similar to B cell receptors of PfMSP1FL-specific MBCs, anti-PfMSP119 IgGs had high levels of amino acid substitutions and their sequences were predominantly found in classical MBCs, not atypical MBCs. Collectively, these results showed evolution of the PfMSP1-specific humoral immune response with cumulative Pf exposure, with a shift from IgM+ to IgG+ B cell memory, diversification of B cells from germline, and stronger recognition of PfMSP1 variants by the plasma IgG repertoire.

B Cell Receptor Repertoire Analysis in Malaria-Naive and Malaria-Experienced Individuals Reveals Unique Characteristics of Atypical Memory B Cells.

Malaria, caused by parasites of the Plasmodium genus, is responsible for significant morbidity and mortality globally. Chronic Plasmodium falciparum exposure affects the B cell compartment, leading to the accumulation of atypical memory B cells (atMBCs). IgM-positive (IgM+) and IgG+ atMBCs have not been compared in-depth in the context of malaria, nor is it known if atMBCs in malaria-experienced individuals are different from phenotypically similar B cells in individuals with no known history of Plasmodium exposure. To address these questions, we characterized the B cell receptor (BCR) repertoire of naive B cells (NBCs), IgM+ and IgG+ classical MBCs (cMBCs), and IgM+ and IgG+ atMBCs from 13 malaria-naive American adults and 7 malaria-experienced Ugandan adults. Our results demonstrate that P. falciparum exposure mainly drives changes in atMBCs. In comparison to malaria-naive adults, the BCR repertoire of Plasmodium-exposed adults showed increased levels of somatic hypermutation in the heavy chain V region in IgM+ and IgG+ atMBCs, shorter heavy chain complementarity-determining region 3 (HCDR3) in IgG+ atMBCs, and increased usage of IGHV3-73 in IgG+ cMBCs and both IgM+ and IgG+ atMBCs. Irrespective of Plasmodium exposure, IgM+ atMBCs closely resembled NBCs, while IgG+ atMBCs resembled IgG+ cMBCs. Physicochemical properties of the HCDR3 seemed to be intrinsic to cell type and independent of malaria experience. The resemblance between atMBCs from Plasmodium-exposed and naive adults suggests similar differentiation pathways regardless of chronic antigen exposure. Moreover, these data demonstrate that IgM+ and IgG+ atMBCs are distinct populations that should be considered separately in future analyses. IMPORTANCE Malaria, caused by Plasmodium parasites, still contributes to a high global burden of disease, mainly in children under 5 years of age. Chronic and recurrent Plasmodium infections affect the development of B cell memory against the parasite and promote the accumulation of atypical memory B cells (atMBCs), which have an unclear function in the immune response. Understanding where these cells originate from and whether they are beneficial in the immune response to Plasmodium will help inform vaccination development efforts. We found differences in B cell receptor (BCR) properties of atMBCs between malaria-naive and malaria-experienced adults that are suggestive of divergent selection processes, resulting in more somatic hypermutation and differential immunoglobulin heavy chain V (IGHV) gene usage. Despite these differences, atMBCs from malaria-naive and malaria-experienced adults also showed many similarities in BCR characteristics, such as physicochemical properties of the HCDR3 region, suggesting that atMBCs undergo similar differentiation pathways in response to different pathogens. Our study provides new insights into the effects of malaria experience on the B cell compartment and the relationships between atMBCs and other B cell populations.

SARS-CoV-2 spike-specific memory B cells express markers of durable immunity after non-severe COVID-19 but not after severe disease.

SARS-CoV-2 infection elicits a robust B cell response, resulting in the generation of long-lived plasma cells and memory B cells. Here, we aimed to determine the effect of COVID-19 severity on the memory B cell response and characterize changes in the memory B cell compartment between recovery and five months post-symptom onset. Using high-parameter spectral flow cytometry, we analyzed the phenotype of memory B cells with reactivity against the SARS-CoV-2 spike protein or the spike receptor binding domain (RBD) in recovered individuals who had been hospitalized with non-severe (n=8) or severe (n=5) COVID-19. One month after symptom onset, a substantial proportion of spike-specific IgG + B cells showed an activated phenotype. In individuals who experienced non-severe disease, spike-specific IgG + B cells showed increased expression of markers associated with durable B cell memory, including T-bet, FcRL5, and CD11c, which was not observed after severe disease. Five months post-symptom onset, the majority of spike-specific memory B cells had a resting phenotype and the percentage of spike-specific T-bet + IgG + memory B cells decreased to baseline levels. Collectively, our results suggest that the memory B cell response elicited during non-severe COVID-19 may be of higher quality than the response after severe disease.

SARS-CoV-2 spike-specific memory B cells express higher levels of T-bet and FcRL5 after non-severe COVID-19 as compared to severe disease.

SARS-CoV-2 infection elicits a robust B cell response, resulting in the generation of long-lived plasma cells and memory B cells. Here, we aimed to determine the effect of COVID-19 severity on the memory B cell response and characterize changes in the memory B cell compartment between recovery and five months post-symptom onset. Using high-parameter spectral flow cytometry, we analyzed the phenotype of memory B cells with reactivity against the SARS-CoV-2 spike protein or the spike receptor binding domain (RBD) in recovered individuals who had been hospitalized with non-severe (n = 8) or severe (n = 5) COVID-19. One month after symptom onset, a substantial proportion of spike-specific IgG+ B cells showed an activated phenotype. In individuals who experienced non-severe disease, spike-specific IgG+ B cells showed increased expression of markers associated with durable B cell memory, including T-bet and FcRL5, as compared to individuals who experienced severe disease. While the frequency of T-bet+ spike-specific IgG+ B cells differed between the two groups, these cells predominantly showed an activated switched memory B cell phenotype in both groups. Five months post-symptom onset, the majority of spike-specific memory B cells had a resting phenotype and the percentage of spike-specific T-bet+ IgG+ memory B cells decreased to baseline levels. Collectively, our results highlight subtle differences in the B cells response after non-severe and severe COVID-19 and suggest that the memory B cell response elicited during non-severe COVID-19 may be of higher quality than the response after severe disease.

Potential functions of atypical memory B cells in Plasmodium-exposed individuals.

Naturally acquired iummunity against clinical malaria is slow to develop, taking years of repeated exposure to parasites to acquire sufficiently broad and potent antibody responses. Increasing evidence suggests that Plasmodium infection and the resulting immune stimulation contribute to changes in the B cell compartment. In particular, accumulation of atypical memory B cells (atMBCs) is common in Plasmodium-exposed individuals. Similarities to B cell subsets present in other acute and chronic disease settings have provided insight into the development and potential function of these cells; however, their contribution to protection against malaria is still poorly understood. Here, we discuss recent findings that have increased our understanding of atMBCs and outline outstanding questions related to their function and development in the protective immune response to malaria.

Naturally Acquired Humoral Immunity Against Plasmodium falciparum Malaria.

Malaria remains a significant contributor to the global burden of disease, with around 40% of the world's population at risk of Plasmodium infections. The development of an effective vaccine against the malaria parasite would mark a breakthrough in the fight to eradicate the disease. Over time, natural infection elicits a robust immune response against the blood stage of the parasite, providing protection against malaria. In recent years, we have gained valuable insight into the mechanisms by which IgG acts to prevent pathology and inhibit parasite replication, as well as the potential role of immunoglobulin M (IgM) in these processes. Here, we discuss recent advances in our understanding of the mechanisms, acquisition, and maintenance of naturally acquired immunity, and the relevance of these discoveries for the development of a potential vaccine against the blood stage of Plasmodium falciparum.

Single nucleotide polymorphism in gene encoding transcription factor Prep1 is associated with HIV-1-associated dementia.

BACKGROUND: Infection with HIV-1 may result in severe cognitive and motor impairment, referred to as HIV-1-associated dementia (HAD). While its prevalence has dropped significantly in the era of combination antiretroviral therapy, milder neurocognitive disorders persist with a high prevalence. To identify additional therapeutic targets for treating HIV-associated neurocognitive disorders, several candidate gene polymorphisms have been evaluated, but few have been replicated across multiple studies. METHODS: We here tested 7 candidate gene polymorphisms for association with HAD in a case-control study consisting of 86 HAD cases and 246 non-HAD AIDS patients as controls. Since infected monocytes and macrophages are thought to play an important role in the infection of the brain, 5 recently identified single nucleotide polymorphisms (SNPs) affecting HIV-1 replication in macrophages in vitro were also tested. RESULTS: The CCR5 wt/Δ32 genotype was only associated with HAD in individuals who developed AIDS prior to 1991, in agreement with the observed fading effect of this genotype on viral load set point. A significant difference in genotype distribution among all cases and controls irrespective of year of AIDS diagnosis was found only for a SNP in candidate gene PREP1 (p = 1.2 × 10(-5)). Prep1 has recently been identified as a transcription factor preferentially binding the -2,518 G allele in the promoter of the gene encoding MCP-1, a protein with a well established role in the etiology of HAD. CONCLUSION: These results support previous findings suggesting an important role for MCP-1 in the onset of HIV-1-associated neurocognitive disorders.

Polymorphism in HIV-1 dependency factor PDE8A affects mRNA level and HIV-1 replication in primary macrophages.

Four genome-wide RNAi screens have recently identified hundreds of HIV-1 dependency factors (HDFs). Previously, we reported a large variation in the ability of HIV-1 to replicate in monocyte-derived macrophages (MDM) derived from >400 healthy seronegative blood donors. Here we determined whether SNPs in genes encoding newly identified HDFs were associated with this variation in HIV-1 replication. We found a significant association between the minor allele of SNP rs2304418 in phosphodiesterase 8A (PDE8A) and lower HIV-1 replication (p=2.4×10(-6)). The minor allele of SNP rs2304418 was also significantly associated with lower PDE8A mRNA levels in MDM (p=8.3×10(-5)). In accordance with this, overexpression of PDE8A in HEK293T cells resulted in increased HIV-1 replication, while subsequent knock-down of PDE8A decreased replication. This study links host genetic variation in a newly identified HDF to variation in HIV-1 replication in a relevant primary target cell for HIV-1 and may provide new leads for treatment of this infection.