SARS-CoV-2 Infections in Vaccinated and Unvaccinated Populations in Camp Lemonnier, Djibouti, from April 2020 to January 2022.

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted the disparity between developed and developing countries for infectious disease surveillance and the sequencing of pathogen genomes. The majority of SARS-CoV-2 sequences published are from Europe, North America, and Asia. Between April 2020 and January 2022, 795 SARS-CoV-2-positive nares swabs from individuals in the U.S. Navy installation Camp Lemonnier, Djibouti, were collected, sequenced, and analyzed. In this study, we described the results of genomic sequencing and analysis for 589 samples, the first published viral sequences for Djibouti, including 196 cases of vaccine breakthrough infections. This study contributes to the knowledge base of circulating SARS-CoV-2 lineages in the under-sampled country of Djibouti, where only 716 total genome sequences are available at time of publication. Our analysis resulted in the detection of circulating variants of concern, mutations of interest in lineages in which those mutations are not common, and emerging spike mutations.

Antibodies generated against Streptococci protect in a mouse model of disseminated aspergillosis.

Invasive aspergillosis (IA) resulting from infection by Aspergillus fumigatus is a leading cause of death in immunosuppressed populations. There are limited therapeutic options for this disease and currently no vaccine. There is evidence that some anti-A. fumigatus mAbs can provide protection against IA. However, vaccine development has been impeded by a paucity of immunological targets on this organism demonstrated to provide protective responses. Sialylated oligosaccharide epitopes found on a variety of pathogens, including fungi and group B streptococci (GBS), are thought to be major virulence factors of these organisms facilitating pathogen attachment to host cells and modulating complement activation and phagocytosis. Because some of these oligosaccharide structures are conserved across kingdoms, we screened a panel of mAbs raised against GBS serotypes for reactivity to A. fumigatus. This approach revealed that SMB19, a GBSIb type-specific mAb, reacts with A. fumigatus conidia and hyphae. The presence of this Ab in mice, as a result of passive or active immunization, or by enforced expression of the SMB19 H chain as a transgene, results in significant protection in both i.v. and airway-induced models of IA. This study demonstrates that some Abs generated against bacterial polysaccharides engage fungal pathogens and promote their clearance in vivo and thus provide rationale of alternative strategies for the development of vaccines or therapeutic mAbs against these organisms.

Natural antibody repertoires: development and functional role in inhibiting allergic airway disease.

In this review we discuss the effects of microbial exposure on the B cell repertoire. Neonatal exposure to conserved bacterial carbohydrates and phospholipids permanently reprograms the natural antibody repertoire directed toward these antigens by clonal expansion, alterations in clonal dominance, and increased serum antibody levels. These epitopes are present not only in bacterial cell walls, but also in common environmental allergens. Neonatal immunization with bacterial polysaccharide vaccines results in attenuated allergic airway responses to fungi-, house dust mite-, and cockroach-associated allergens in mouse models. The similarities between mouse and human natural antibody repertoires suggest that reduced microbial exposure in children may have the opposite effect, providing a potential mechanistic explanation for the hygiene hypothesis. We propose that understanding the effects of childhood infections on the natural antibody repertoire and the mechanisms of antibody-mediated immunoregulation observed in allergy models will lead to the development of prevention/interventional strategies for treatment of allergic asthma.

Antibodies generated against conserved antigens expressed by bacteria and allergen-bearing fungi suppress airway disease.

There has been a sharp rise in allergic asthma and asthma-related deaths in the developed world, in contrast to many childhood illnesses that have been reduced or eliminated. The hygiene hypothesis proposes that excessively sanitary conditions early in life result in autoimmune and allergic phenomena because of a failure of the immune system to receive proper microbial stimulation during development. We demonstrate that Abs generated against conserved bacterial polysaccharides are reactive with and dampen the immune response against chitin and Aspergillus fumigatus. A reduction in Ag uptake, cell influx, cell activation, and cytokine production occurred in the presence of anti-polysaccharide Abs, resulting in a striking decrease in the severity of allergic airway disease in mice. Overall, our results suggest that Ag exposure--derived from environmental sources, self-antigens, or vaccination--during the neonatal period has dramatic effects on the adult Ab response and modifies the development of allergic airway disease.

Cathelin-related antimicrobial peptide differentially regulates T- and B-cell function.

Mammalian antimicrobial peptides (AMPs) play an important role in host defense via direct antimicrobial activity as well as immune regulation. The mouse cathelin-related antimicrobial peptide (mCRAMP), produced from the mouse gene Camp, is the only mouse cathelicidin identified and the ortholog of the human gene encoding the peptide LL-37. This study tested the hypothesis that mouse B and T cells produce and respond to mCRAMP. We show that all mature mouse B-cell subsets, including follicular (FO), marginal zone (MZ), B1a, and B1b cells, as well as CD4(+) and CD8(+) T cells produce Camp mRNA and mCRAMP protein. Camp(-/-) B cells produced equivalent levels of IgM, IgG3, and IgG2c but less IgG1 and IgE, while Camp(-/-) CD4(+) T cells cultured in Th2-inducing conditions produced more IL-4-expressing cells when compared with WT cells, effects that were reversed upon addition of mCRAMP. In vivo, Camp(-/-) mice immunized with TNP-OVA absorbed in alum produced an enhanced TNP-specific IgG1 response when compared with WT mice. ELISpot analysis revealed increased numbers of TNP-specific IgG1-secreting splenic B cells and FACS analysis revealed increased CD4(+) T-cell IL-4 expression. Our results suggest that mCRAMP differentially regulates B- and T-cell function and implicate mCRAMP in the regulation of adaptive immune responses.

Modification of the zone of polarizing activity signal by trypsin.

Patterning of the developing vertebrate limb along the anterior-posterior axis is controlled by the zone of polarizing activity (ZPA) via the expression of Sonic hedgehog (Shh) and along the proximal-distal axis by the apical ectodermal ridge (AER) through the production of fibroblast growth factors (FGFs). ZPA grafting, as well as ectopic application of SHH to the anterior chick limb bud, demonstrate that digit patterning is largely influenced by these secreted factors. Although signal transduction pathways have been well characterized for SHH and for FGFs, little is known of how these signals are regulated extracellularly in the limb. The present study shows that alteration of the extracellular environment through trypsin treatment can have profound effects on digit patterning. These effects appear to be mediated by the induction of Shh in host tissues and by ectopic AER formation, implicating the extracellular matrix in regulating the signaling activities of key patterning genes in the limb.