Plasmodium parasite-specific antibodies are critical for protection against malaria, yet the development of long-lived and effective humoral immunity against Plasmodium takes many years and multiple rounds of infection and cure. Here, we report that the rapid development of short-lived plasmablasts during experimental malaria unexpectedly hindered parasite control by impeding germinal center responses. Metabolic hyperactivity of plasmablasts resulted in nutrient deprivation of the germinal center reaction, limiting the generation of memory B cell and long-lived plasma cell responses. Therapeutic administration of a single amino acid to experimentally infected mice was sufficient to overcome the metabolic constraints imposed by plasmablasts and enhanced parasite clearance and the formation of protective humoral immune memory responses. Thus, our studies not only challenge the current model describing the role and function of blood-stage Plasmodium-induced plasmablasts but they also reveal new targets and strategies to improve anti-Plasmodium humoral immunity.

Many autoimmune and infectious diseases are characterized by the formation of granulomas which are inflammatory lesions that consist of spatially organized immune cells. These sites protect the host and control pathogens like Mycobacterium tuberculosis (Mtb), but are highly inflammatory and cause pathology. Using bacille Calmette-Guerin (BCG) and Mtb infection in mice that induce sarcoid or caseating granulomas, we show that a subpopulation of granuloma macrophages produces vascular endothelial growth factor (VEGF-A), which recruits immune cells to the granuloma by a non-angiogenic pathway. Selective blockade of VEGF-A in myeloid cells, combined with granuloma transplantation, shows that granuloma VEGF-A regulates granulomatous inflammation. The severity of granuloma-related inflammation can be ameliorated by pharmaceutical or genetic inhibition of VEGF-A, which improves survival of mice infected with virulent Mtb without altering host protection. These data show that VEGF-A inhibitors could be used as a host-directed therapy against granulomatous diseases like tuberculosis and sarcoidosis, thereby expanding the value of already existing and approved anti-VEGF-A drugs.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Previous research has evaluated antibody responses toward an influenza virus vaccine in the context of deficiencies for vitamins A and D (VAD+VDD). Results showed that antibodies and antibody-forming cells in the respiratory tract were reduced in VAD+VDD mice. However, effectors were recovered when oral supplements of vitamins A + D were delivered at the time of vaccination. Here we address the question of how vaccine-induced CD8+ T cell responses are affected by deficiencies for vitamins A + D. VAD+VDD and control mice were vaccinated with an intranasal, cold-adapted influenza virus A/Puerto Rico/8/34 vaccine, with or without oral supplements of vitamins A + D. Results showed that the percentages of vaccine-induced CD8+ T cell and total CD4+ T cell responses were low among lymphocytes in the airways of VAD+VDD animals compared to controls. The CD103 membrane marker, a protein that binds e-cadherin (expressed on respiratory tract epithelial cells), was unusually high on virus-specific T cells in VAD+VDD mice compared to controls. Interestingly, when T cells specific for the PA224-233/Db epitope were compared with T cells specific for the NP366-374/Db epitope, the former population was more strongly positive for CD103. Preliminary experiments revealed normal or above-normal percentages for vaccine-induced T cells in airways when VAD+VDD animals were supplemented with vitamins A + D at the time of vaccination and on days 3 and 7 after vaccination. Our results suggest that close attention should be paid to levels of vitamins A and D among vaccine recipients in the clinical arena, as low vitamin levels may render individuals poorly responsive to vaccines.

As the first step in the recruitment of neutrophils into tissues, the cells become tethered to and roll on the vessel wall. These processes are mediated by interactions between the P- and E-selectins, expressed on the endothelial cells of the vessel wall, and their ligands, expressed on the neutrophils. Recently, we reported that CD43 on activated T cells functions as an E-selectin ligand and thereby mediates T cell migration to inflamed sites, in collaboration with P-selectin glycoprotein ligand-1 (PSGL-1), a major P- and E-selectin ligand. Here, we examined whether CD43 on neutrophils also functions as an E-selectin ligand. CD43 was precipitated with an E-selectin-IgG chimera from mouse bone marrow neutrophils. A CD43 deficiency diminished the E-selectin-binding activity of neutrophils when PSGL-1 was also deficient. Intravital microscopy showed that the CD43 deficiency significantly increased leukocyte rolling velocities in TNF-alpha-stimulated venules blocked with an anti-P-selectin mAb, where the rolling was mostly E-selectin dependent, when PSGL-1 was also absent. In contrast, in venules with trauma-induced inflammation, where the rolling was largely P-selectin dependent, the CD43 deficiency reduced leukocyte rolling velocities. Collectively, these observations suggest that CD43 generally serves as an antiadhesive molecule to attenuate neutrophil-endothelial interactions, but when E-selectin is expressed on endothelial cells, it also plays a proadhesive role as an E-selectin ligand.

During acquired immunity to Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection in mice, dendritic cells (DCs) present mycobacterial antigens to naive T cells to prime an immune response. Complement C5a (anaphylatoxin) secreted by mycobacteria-infected macrophages regulates IL-12p70 production. As IL-12p70 regulates Th1 immunity against mycobacteria in mice, we examined the effects of C5a on IL-12p70 secretion by murine DCs and Th1 immunity. DCs cultured from C5-deficient (C5(-/-)) and -sufficient (C5(+/+)) mice were infected with BCG in the presence or absence of the C5a peptide. ELISA showed that C5(-/-) DCs secreted less IL-12p70 (600 pg/mL vs. 100 pg/mL) than C5(+/+) DCs, and they secreted more IL-10. Using immunophenotyping, reduced CD40 expression was found on C5(-/-) DCs after BCG infection. BCG-primed DCs were then cocultured with naive or BCG-immune T cells to differentiate them into IFN-gamma-secreting Th1 T cells. Coincident with increased IL-12p70 levels, BCG-primed C5(+/+) DCs cocultured with naive or immune C5(+/+) T cells showed a larger increase in CD4+ IFN-gamma/CD8+ IFN-gamma+ T cells compared with cocultured DCs and T cells from C5(-/-) mice. Thus, BCG-primed C5(+/+) DCs were better able to drive a Th1 response. Furthermore, BCG aerosol-infected C5(-/-) mice showed reduced CD4 and CD8 IFN-gamma-secreting T cells in the lungs, concurrent with an increased growth of BCG. Thus, C5a, an innate peptide, appears to play an important role in the generation of acquired immune responses in mice by regulating the Th1 response through modulation of IL-12p70 secretion from DCs.