Evolution of STAT2 resistance to flavivirus NS5 occurred multiple times despite genetic constraints.

Zika and dengue virus nonstructural protein 5 antagonism of STAT2, a critical interferon signaling transcription factor, to suppress the host interferon response is required for viremia and pathogenesis in a vertebrate host. This affects viral species tropism, as mouse STAT2 resistance renders only immunocompromised or humanized STAT2 mice infectable. Here, we explore how STAT2 evolution impacts antagonism. By measuring the susceptibility of 38 diverse STAT2 proteins, we demonstrate that resistance arose numerous times in mammalian evolution. In four species, resistance requires distinct sets of multiple amino acid changes that often individually disrupt STAT2 signaling. This reflects an evolutionary ridge where progressive resistance is balanced by the need to maintain STAT2 function. Furthermore, resistance may come with a fitness cost, as resistance that arose early in lemur evolution was subsequently lost in some lemur lineages. These findings underscore that while it is possible to evolve resistance to antagonism, complex evolutionary trajectories are required to avoid detrimental host fitness consequences.

Expression of CD117 (c-Kit) on Circulating B Cells in Pediatric Schistosomiasis.

Few B cells express CD27, the primary marker for memory B cells, in pediatric schistosomiasis, suggesting B cell malfunction. This study further demonstrates unexpected high expression of CD117 on circulating B cells in children highly exposed to Schistosoma mansoni infectious larvae. CD117 is expressed by immature or lymphoma B cells, but not by mature, circulating cells. We therefore sought to define the significance of CD117 on blood B cells. We found that CD117-positive (CD117+) B cells increased with the intensity of schistosome infection. In addition, CD117 expression was reduced on CD23+ B cells previously shown to correlate with resistance to infection. Stimulation with a panel of cytokines demonstrated that CD117 levels were upregulated in response to a combination of interleukin 4 (IL-4) and stem cell factor (SCF), the ligand for CD117, whereas IL-2 led to a reduction. In addition, stimulation with SCF generally reduced B cell activation levels. Upon further investigation, it was established that multiple circulating cells expressed increased levels of CD117, including monocytes, neutrophils, and eosinophils, and expression levels correlated with that of B cells. Finally, we identified a population of large circulating cells with features of reticulocytes. Overall, our results suggest that hyperexposure to intravascular parasitic worms elicits immature cells from the bone marrow. Levels of SCF were shown to reduce as children began to transition through puberty. The study results pose an explanation for the inability of children to develop significant immunity to infection until after puberty.

Potential Utility of Systemic Plasma Biomarkers for Evaluation of Pediatric Schistosomiasis in Western Kenya.

Introduction: Current diagnostic tools for schistosomiasis are limited, and new tests are necessary to enhance disease diagnosis and surveillance. Identification of novel disease-specific biomarkers may facilitate the development of such tests. We evaluated a panel of biomarkers used in sepsis and parasitic diseases for their potential suitability in the diagnosis of schistosomiasis. Objective: The study evaluated the levels of systemic plasma biomarkers in relation to Schistosoma mansoni infection and parasite burden. Methods: Six biomarkers were measured in the plasma of children from schistosomiasis-endemic regions using ELISA. The concentration of soluble CD23 (sCD23) and lipopolysaccharide (LPS) was tested in 199 and 124 plasma samples, respectively, while interleukin-6 (IL-6), soluble triggering receptor expressed on myeloid (sTREM) cells, eotaxin-1, and fatty acid-binding protein (FABP) concentrations were tested in 30 plasma samples. Results: The concentration of IL-6, eotaxin-1, FABP, and LPS was similar between schistosome-infected and uninfected children. The schistosome-infected children had higher median levels of sTREM and sCD23 as compared to uninfected children, 119.0 (29.9-208.9) versus 10.7 (0.0-73.4) (p = 0.046) and 2,549.0 (1,899.0-3,356.0) vs. 2,035.0 (1,448.0-2,939.0) (p = 0.05), respectively. In addition, sTREM was positively correlated with egg density (p = 0.017). Conclusion: Our data show that active schistosomiasis per se is associated with elevated levels of sTREM and sCD23. sTREM has potential diagnostic and prognostic values. However, these biomarkers did not distinguish between children with low egg burden and uninfected children.