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Cytokines and chemokines are immune response molecules that display diverse functions, such as inflammation and immune regulation. In Plasmodium vivax infections, the uncontrolled production of these molecules is thought to contribute to pathogenesis and has been proposed as a possible predictor for disease complications. The objective of this study was to evaluate the cytokine profile of P . vivax malaria patients with different clinical outcomes to identify possible immune biomarkers for severe P . vivax malaria. The study included patients with non-severe (n = 56), or severe (n = 50) P . vivax malaria and healthy controls (n = 50). Patient plasma concentrations of IL-4, IL-2, CXCL10, IL-1β, TNF-α, CCL2, IL-17A, IL-6, IL-10, IFN-γ, IL-12p70, CXCL8 and active TGF-β1 were determined through flow cytometry. The levels of several cytokines and chemokines, CXCL10, IL-10, IL-6, IL-4, CCL2 and IFN-γ were found to be significantly higher in severe, compared to non-severe P . vivax malaria patients. Severe thrombocytopenia was positively correlated with IL-4, CXCL10, IL-6, IL-10 and IFN-γ levels, renal dysfunction was related to an increase in IL-2, IL-1β, IL-17A and IL-8, and hepatic impairment with CXCL10, MCP-1, IL-6 and IFN-γ. A Lasso regression model suggests that IL-4, IL-10, CCL2 and TGF-β might be developed as biomarkers for severity in P . vivax malaria. Severe P . vivax malaria patients present specific cytokine and chemokine profiles that are different from non-severe patients and that could potentially be developed as biomarkers for disease severity.

Anemia caused by trypanosome infection is poorly understood. Autoimmunity during Trypanosoma brucei infection was proposed to have a role during anemia, but the mechanisms involved during this pathology have not been elucidated. In mouse models and human patients infected with malaria parasites, atypical B-cells promote anemia through the secretion of autoimmune anti-phosphatidylserine (anti-PS) antibodies that bind to uninfected erythrocytes and facilitate their clearance. Using mouse models of two trypanosome infections, Trypanosoma brucei and Trypanosoma cruzi , we assessed levels of autoantibodies and anemia. Our results indicate that acute T . brucei infection, but not T . cruzi , leads to early increased levels of plasma autoantibodies against different auto antigens tested (PS, DNA and erythrocyte lysate) and expansion of atypical B cells (ABCs) that secrete these autoantibodies. In vitro studies confirmed that a lysate of T . brucei , but not T . cruzi , could directly promote the expansion of these ABCs. PS exposure on erythrocyte plasma membrane seems to be an important contributor to anemia by delaying erythrocyte recovery since treatment with an agent that prevents binding to it (Annexin V) ameliorated anemia in T . brucei -infected mice. Analysis of the plasma of patients with human African trypanosomiasis (HAT) revealed high levels of anti-PS antibodies that correlated with anemia. Altogether these results suggest a relation between autoimmunity against PS and anemia in both mice and patients infected with T . brucei .

Autoimmunity is a common phenomenon reported in many globally relevant infections, including malaria and COVID-19. These and other highly inflammatory diseases have been associated with the presence of autoantibodies. The role that these autoantibodies play during infection has been an emerging topic of interest. The vast numbers of studies reporting a range of autoantibodies targeting cellular antigens, such as dsDNA and lipids, but also immune molecules, such as cytokines, during malaria, COVID-19 and other infections, underscore the importance that autoimmunity can play during infection. During both malaria and COVID-19, the presence of autoantibodies has been correlated with associated pathologies such as malarial anemia and severe COVID-19. Additionally, high levels of Atypical/Autoimmune B cells (ABCs and atypical B cells) have been observed in both diseases. The growing literature of autoimmune B cells, age-associated B cells and atypical B cells in Systemic Lupus erythematosus (SLE) and other autoimmune disorders has identified recent mechanistic and cellular targets that could explain the development of autoantibodies during infection. These new findings establish a link between immune responses during infection and autoimmune disorders, highlighting shared mechanistic insights. In this review, we focus on the recent evidence of autoantibody generation during malaria and other infectious diseases and their potential pathological role, exploring possible mechanisms that may explain the development of autoimmunity during infections.

Differences in immune responses to viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) can show sexual dimorphism. Age-associated B cells (ABC) are a population of CD11c + T-bet + B cells critical for antiviral responses and autoimmune disorders. Absence of DEF6 and SWAP-70, two homologous guanine exchange factors, in double-knock-out (DKO) mice leads to a lupus-like syndrome in females marked by accumulation of ABCs. Here we demonstrate that DKO ABCs show sex-specific differences in cell number, upregulation of an ISG signature, and further differentiation. DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c + and CD11c − effector B cell populations with pathogenic and pro-inflammatory function as demonstrated by BCR sequencing and fate-mapping experiments. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs, resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function and differentiation of ABCs that accompanies TLR7-driven immunopathogenesis. Autoimmunity mediated by age-associated B cells (ABC) can affect males and females differently. Here, using a lupus-like mouse model that affects females more severely, the authors observe an ABC mediated and guanine nucleotide exchange factor (GEF) restrained pathogenic process involving TLR7.

Early-career researchers from Spanish-speaking Latin American countries and small U.S. universities are underrepresented in international scientific databases. They have geographical importance, infectious disease endemicity, and exceptional researchers in microbiology, but these factors do not translate to representation in high-impact scientific publications. Many reasons could be involved, including financial burdens such as the inability to pay article processing charges. Additional teaching, institutional, and service responsibilities also highly influence their research productivity. Despite this, they are expected to publish high-impact articles, and their career development highly depends on it. There is an opportunity for global peer collaboration to tackle this inequity and uplift underrepresented scientists, which will ultimately provide benefits and sustainability to the global microbial sciences.

Plasmodium vivax is the most widely distributed human protozoan in the world. It is a causative agent of malaria, with thrombocytopenia being a frequent complication. This study aimed to evaluate the effect of P. vivax infection on plasma cytokine/chemokine levels and anti-phosphatidylserine (anti-PS) autoantibodies, to explore their potential role in thrombocytopenia during P. vivax malaria in Córdoba, Colombia. We included patients with P. vivax malaria and thrombocytopenia (MT); patients with malaria without thrombocytopenia (M) and healthy controls (HC). Plasma cytokines/chemokines (IL-2, IL-4, IL-1β, TNF-α, IL-17A, IL-6, IL-10, IFNγ, IL-12p70, TGF-β1/IP-10, MCP-1, IL-8) were quantified. Evaluation of autoantibodies was performed by ELISA, using phosphatidylserine (PS) as the antigen. IFNγ, IL-6, and IL-10 were found to increase in the MT group (P < 0.05), whereas TGF-β1 was increased in the M group (P < 0.0001). Anti-PS antibody levels were also higher in the MT group and showed a negative correlation with platelet counts. These findings suggest that thrombocytopenia in P. vivax malaria may result from autoantibodies targeting phosphatidylserine on activated platelets, driven by a pro-inflammatory cytokine imbalance, with TGF-β1 potentially exerting a protective effect.

Anemia is a common complication of malaria that is characterized by the loss of infected and uninfected erythrocytes. In mouse malaria models, clearance of uninfected erythrocytes is promoted by autoimmune anti-phosphatidylserine (PS) antibodies produced by T-bet+B-cells, which bind to exposed PS in erythrocytes, but the mechanism in patients is still unclear. In Plasmodium falciparum patients with anemia, we show that atypical memory FcRL5+T-bet+ B-cells are expanded and associate both with higher levels of anti-PS antibodies in plasma and with the development of anemia in these patients. No association of anti-PS antibodies or anemia with other B-cell subsets and no association of other antibody specificities with FcRL5+T-bet+ B-cells is observed, revealing high specificity in this response. We also identify FcRL5+T-bet+ B-cells as producers of anti-PS antibodies in ex vivo cultures of naïve human peripheral blood mononuclear cells (PBMC) stimulated with P.-falciparum-infected erythrocyte lysates. These data define a crucial role for atypical memory B-cells and anti-PS autoantibodies in human malarial anemia.

Zika virus infection is associated with the development of Guillain-Barré syndrome (GBS), a neurological autoimmune disorder caused by immune recognition of gangliosides and other components at nerve membranes. Using a high-throughput ELISA, we have analyzed the anti-glycolipid antibody profile, including gangliosides, of plasma samples from patients with Zika infections associated or not with GBS in Salvador, Brazil. We have observed that Zika patients that develop GBS present higher levels of anti-ganglioside antibodies when compared to Zika patients without GBS. We also observed that a broad repertoire of gangliosides was targeted by both IgM and IgG anti-self antibodies in these patients. Since Zika virus infects neurons, which contain membrane gangliosides, antigen presentation of these infected cells may trigger the observed autoimmune anti-ganglioside antibodies suggesting direct infection-induced autoantibodies as a cause leading to GBS development. Collectively, our results establish a link between anti-ganglioside antibodies and Zika-associated GBS in patients.

Malaria caused by Plasmodium vivax is a highly prevalent infection world-wide, that was previously considered mild, but complications such as anemia have been highly reported in the past years. In mice models of malaria, anti-phosphatidylserine (anti-PS) autoantibodies, produced by atypical B-cells, bind to uninfected erythrocytes and contribute to anemia. In human patients with P. falciparum malaria, the levels of anti-PS, atypical B-cells and anemia are strongly correlated to each other. In this study, we focused on assessing the relationship between autoantibodies, different B-cell populations and hemoglobin levels in two different cohorts of P. vivax patients from Colombia, South America. In a first longitudinal cohort, our results show a strong inverse correlation between different IgG autoantibodies tested (anti-PS, anti-DNA and anti-erythrocyte) and atypical memory B-cells (atMBCs) with hemoglobin in both P. vivax and P. falciparum patients over time. In a second cross-sectional cohort, we observed a stronger relation between hemoglobin levels, atMBCs and autoantibodies in complicated P. vivax patients compared to uncomplicated ones. Altogether, these data constitute the first evidence of autoimmunity associating with anemia and complicated P. vivax infections, suggesting a role for its etiology through the expansion of autoantibody-secreting atMBCs.

Zika virus (ZIKV) disease has become a global health emergency with devastating effects on public health. Recent evidences implicate the virus as an emergent neuropathological agent promoting serious pathologies of the human nervous system, that include destructive and malformation consequences such as development of ocular and fetal brain lesions, microcephaly in neonates, and Guillain-Barré syndrome (GBS) in adults. These neurological disorders of both central and peripheral nervous systems are thought to be associated to the neurotropic properties of the virus that has ability to infect neural stem cells as well as peripheral neurons, a hallmark of its pathogenicity. The presence of autoantibodies against gangliosides plays a pivotal role in the etiogenesis of GBS and a variety of neurological disorders. Gangliosides are a class of galactose-containing cerebrosides mainly expressed in nervous system tissues playing a critical role in the physiology of neural cells and neurogenesis. Herein, our findings indicate that patients at acute phase of ZIKV infection without any neurological signs show increased levels of IgG autoantibody against GD3 gangliosides, a class of glycolipid found to be highly expressed in neural stem cell acting in the maintenance of their self-renewal cellular capacity. It is possible that a pathological threshold of these antibodies is only acquired in secondary or subsequent infections. In the light of these evidences, we propose that the target of GD3 by autoimmune responses may possibly has an effect in the neuropathy and neurogenesis disorder seen during ZIKV infection.