IgA deficiency destabilizes homeostasis toward intestinal microbes and increases systemic immune dysregulation.

The ability of most patients with selective immunoglobulin A (IgA) deficiency (SIgAD) to remain apparently healthy has been a persistent clinical conundrum. Compensatory mechanisms, including IgM, have been proposed, yet it remains unclear how secretory IgA and IgM work together in the mucosal system and, on a larger scale, whether the systemic and mucosal anti-commensal responses are redundant or have unique features. To address this gap in knowledge, we developed an integrated host-commensal approach combining microbial flow cytometry and metagenomic sequencing (mFLOW-Seq) to comprehensively define which microbes induce mucosal and systemic antibodies. We coupled this approach with high-dimensional immune profiling to study a cohort of pediatric patients with SIgAD and household control siblings. We found that mucosal and systemic antibody networks cooperate to maintain homeostasis by targeting a common subset of commensal microbes. In IgA-deficiency, we find increased translocation of specific bacterial taxa associated with elevated levels of systemic IgG targeting fecal microbiota. Associated features of immune system dysregulation in IgA-deficient mice and humans included elevated levels of inflammatory cytokines, enhanced follicular CD4 T helper cell frequency and activation, and an altered CD8 T cell activation state. Although SIgAD is clinically defined by the absence of serum IgA, the symptomatology and immune dysregulation were concentrated in the SIgAD participants who were also fecal IgA deficient. These findings reveal that mucosal IgA deficiency leads to aberrant systemic exposures and immune responses to commensal microbes, which increase the likelihood of humoral and cellular immune dysregulation and symptomatic disease in patients with IgA deficiency.

Human T follicular helper clones seed the germinal center-resident regulatory pool.

The mechanisms by which FOXP3+ T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, and localization, we used paired TCRVA/TCRVB sequencing to distinguish tonsillar Tfr cells that are clonally related to natural regulatory T cells (nTfr) from those likely induced from T follicular helper (Tfh) cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were used to pinpoint their in situ locations via multiplex microscopy and establish their divergent functional roles. In silico analyses and in vitro tonsil organoid tracking models corroborated the existence of separate Treg-to-nTfr and Tfh-to-iTfr developmental trajectories. Our results identify human iTfr cells as a distinct CD38+, germinal center-resident, Tfh-descended subset that gains suppressive function while retaining the capacity to help B cells, whereas CD38- nTfr cells are elite suppressors primarily localized in follicular mantles. Interventions differentially targeting specific Tfr cell subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases.

Health and education concerns about returning to campus and online learning during the COVID-19 pandemic among US undergraduate STEM majors.

OBJECTIVE: We examined undergraduates' concerns about returning to campus and online learning from home. PARTICIPANTS: Undergraduates majoring in STEM (Science, Technology, Engineering, and Mathematics) at US universities/colleges. METHODS: Participants completed an online survey in July 2020. We content-analyzed responses to open-ended questions about concerns about fall 2020. RESULTS: Students (N = 64) were 52% women, 47% low socioeconomic status (SES), and 27% non-Hispanic white. Concerns about returning to campus included student noncompliance with university COVID-19 prevention guidelines (28%), infection risk (28%), poor instructional quality (26%), inadequate university plans for preventing/handling outbreaks (25%), negative impacts on social interactions (11%), and transportation/commuting (11%). Concerns about learning from home included difficulty focusing on schoolwork (58%), lack of hands-on/experiential learning (24%), negative impacts on social interactions (19%), family/home environment (15%), concerns that online learning wastes time/money (10%), and inadequate technology/Internet access (5%). CONCLUSIONS: Universities should address student concerns and provide resources to overcome barriers to effective learning.

Historical Contingency Drives Compensatory Evolution and Rare Reversal of Phage Resistance.

Bacteria and lytic viruses (phages) engage in highly dynamic coevolutionary interactions over time, yet we have little idea of how transient selection by phages might shape the future evolutionary trajectories of their host populations. To explore this question, we generated genetically diverse phage-resistant mutants of the bacterium Pseudomonas syringae. We subjected the panel of mutants to prolonged experimental evolution in the absence of phages. Some populations re-evolved phage sensitivity, whereas others acquired compensatory mutations that reduced the costs of resistance without altering resistance levels. To ask whether these outcomes were driven by the initial genetic mechanisms of resistance, we next evolved independent replicates of each individual mutant in the absence of phages. We found a strong signature of historical contingency: some mutations were highly reversible across replicate populations, whereas others were highly entrenched. Through whole-genome sequencing of bacteria over time, we also found that populations with the same resistance gene acquired more parallel sets of mutations than populations with different resistance genes, suggesting that compensatory adaptation is also contingent on how resistance initially evolved. Our study identifies an evolutionary ratchet in bacteria-phage coevolution and may explain previous observations that resistance persists over time in some bacterial populations but is lost in others. We add to a growing body of work describing the key role of phages in the ecological and evolutionary dynamics of their host communities. Beyond this specific trait, our study provides a new insight into the genetic architecture of historical contingency, a crucial component of interpreting and predicting evolution.

STEM undergraduates' perspectives of instructor and university responses to the COVID-19 pandemic in Spring 2020.

OBJECTIVES: We examined undergraduate STEM students' experiences during Spring 2020 when universities switched to remote instruction due to the COVID-19 pandemic. Specifically, we sought to understand actions by universities and instructors that students found effective or ineffective, as well as instructor behaviors that conveyed a sense of caring or not caring about their students' success. METHODS: In July 2020 we conducted 16 focus groups with STEM undergraduate students enrolled in US colleges and universities (N = 59). Focus groups were stratified by gender, race/ethnicity, and socioeconomic status. Content analyses were performed using a data-driven inductive approach. RESULTS: Participants (N = 59; 51% female) were racially/ethnically diverse (76% race/ethnicity other than non-Hispanic white) and from 32 colleges and universities. The most common effective instructor strategies mentioned included hybrid instruction (35%) and use of multiple tools for learning and student engagement (27%). The most common ineffective strategies mentioned were increasing the course workload or difficulty level (18%) and use of pre-recorded lectures (15%). The most common behaviors cited as making students feel the instructor cared about their success were exhibiting leniency and/or flexibility regarding course policies or assessments (29%) and being responsive and accessible to students (25%). The most common behaviors cited as conveying the instructors did not care included poor communication skills (28%) and increasing the difficulty of the course (15%). University actions students found helpful included flexible policies (41%) and moving key services online (e.g., tutoring, counseling; 24%). Students felt universities should have created policies for faculty and departments to increase consistency (26%) and ensured communication strategies were honest, prompt, and transparent (23%). CONCLUSIONS: To be prepared for future emergencies, universities should devise evidence-based policies for remote operations and all instructors should be trained in best practices for remote instruction. Research is needed to identify and ameliorate negative impacts of the pandemic on STEM education.