Monomeric IgA Antagonizes IgG-Mediated Enhancement of DENV Infection

Dengue virus (DENV) is a prevalent human pathogen, infecting approximately 400 million individuals per year and causing symptomatic disease in approximately 100 million. A distinct feature of dengue is the increased risk for severe disease in some individuals with preexisting DENV-specific immunity. One proposed mechanism for this phenomenon is antibody-dependent enhancement (ADE), in which poorly-neutralizing IgG antibodies from a prior infection opsonize DENV to increase infection of Fc gamma receptor-bearing cells. While IgM and IgG are the most commonly studied DENV-reactive antibody isotypes, our group and others have described the induction of DENV-specific serum IgA responses during dengue. We hypothesized that monomeric IgA would be able to neutralize DENV without the possibility of ADE. To test this, we synthesized IgG and IgA versions of two different DENV-reactive monoclonal antibodies. We demonstrate that isotype-switching does not affect the antigen binding and neutralization properties of the two mAbs. We show that DENV-reactive IgG, but not IgA, mediates ADE in Fc gamma receptor-positive K562 cells. Furthermore, we show that IgA potently antagonizes the ADE activity of IgG. These results suggest that levels of DENV-reactive IgA induced by DENV infection might regulate the overall IgG mediated ADE activity of DENV-immune plasma in vivo, and may serve as a predictor of disease risk

Transplantation of multipotent progenitors from the adult olfactory epithelium

MAMMALIAN olfactory epithelium produces new neurons rapidly throughout adulthood. Here, we demonstrate that precursor cells harvested from the adult olfactory epithelium, when transplanted into the nasal mucosa of host rats exposed previously to an olfactotoxic gas, engraft and participate in neuroepithelial reconstitution. In contrast to their normal neuronal fate in situ, grafted precursors harvested from bulbectomized donors produced non-neuronal cells as well as neurons. These results demonstrate that epithelial precursors activated following olfactory bulbectomy are not irreversibly committed to making neurons. Thus, olfactory progenitors are subject to a form of feedback control in vivo that regulates the types of cells that they produce within a broader-than-neuronal repertoire

Identification of Mutations that Encode Drug Resistance in the Polymerase Gene of the Human Immunodeficiency Virus

In vitro selection in MT-4 cells was used to generate human immunodeficiency virus-type 1 (HIV 1) variants that are resistant to 2',3'-dideoxycytidine (ddC), 2',3'-didcoxyinosine (ddI) and the (-) enantiomer of 2' ,3'-dideoxy-3'-thiacytidine (3TC). The complete reverse transcriptase open reading frames of these viruses, and portions of flanking protease and integrase within the pol gene, were cloned and sequenced by polymerase chain reaction (PCR) techniques. Mulalions were observed at each of amino acid sites 65 (Lys → Arg: AAA → AGA) and 184 (Met → Val: ATG → GTG) when ddC was used in this protocol, and at site 184 only when either 3TC or ddl was employed. These mutations were introduced into the pol gene of infectious recombinant HXB2-D DNA by site-directed mutagenesis to confirm, by viral replication assay, their importance in conferring resistance against these drugs. A recombinant virus containing the site 65 mutation only possessed greater than 10-fold resistance against ddC compared with parental HXB2-D. Moreover, cross-resistance of about 20-fold and threefold, respectively, was delectable against 3TC and dell but not against 3'-azido-3'-deoxthymidine (AZT). When the 65 and 184 mutations were combined into HXB2-D, the resultant construct did not possess higher levels of resistance lo any of these drugs than observed with the site 65 or 184 mutation alone. These mutations were further demonstrated by PCH analysis of peripheral blood mononuclear cells from 10 patients on long term ddC therapy, although variable patterns were observed in terms of which of the two mutations or both were present. Sometimes, the wild-type site 65 codon was also detected, indicating the presence of mixtures of viral quasi-species. Direct cloning and sequencing revealed the site 65 mutation in viruses isolated from patients on prolonged ddC therapy

Persistent COVID-19 Symptoms Minimally Impact the Development of SARS-CoV-2-Specific T Cell Immunity

SARS-CoV-2 represents an unprecedented public health challenge. While the majority of SARS-CoV-2-infected individuals with mild-to-moderate COVID-19 resolve their infection with few complications, some individuals experience prolonged symptoms lasting for weeks after initial diagnosis. Persistent viral infections are commonly accompanied by immunologic dysregulation, but it is unclear if persistent COVID-19 impacts the development of virus-specific cellular immunity. To this end, we analyzed SARS-CoV-2-specific cellular immunity in convalescent COVID-19 patients who experienced eight days or fewer of COVID-19 symptoms or symptoms persisting for 18 days or more. We observed that persistent COVID-19 symptoms were not associated with the development of an overtly dysregulated cellular immune response. Furthermore, we observed that reactivity against the N protein from SARS-CoV-2 correlates with the amount of reactivity against the seasonal human coronaviruses 229E and NL63. These results provide insight into the processes that regulate the development of cellular immunity against SARS-CoV-2 and related human coronaviruses

A peptide from the Japanese encephalitis virus failed to induce the production of anti-N-methyl-d-aspartate receptor antibodies via molecular mimicry in mice

Background: The development of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis following viral encephalitis, such as Japanese encephalitis, has received increasing attention in recent years. However, the mechanism of anti-NMDAR antibody production following Japanese encephalitis has not been explored. Methods: A peptide from the Japanese encephalitis virus (JEV), which shares a similar amino acid sequence with GluN1, was identified by sequence comparison. We then explored whether active subcutaneous immunization with the JEV peptide could induce the production of anti-NMDAR antibodies and related pathophysiological and behavioral changes in mice. In addition, a published active immune model of anti-NMDAR encephalitis using a GluN1 peptide was used as the positive control. Results: A 6-amino-acid sequence with 83 % similarity between the envelope protein of the JEV (HGTVVI) and GluN1 (NGTHVI) was identified, and the sequence included the N368/G369 region. Active immunization with the JEV peptide induced a substantial and specific immune response in mice. However, anti-NMDAR antibodies were not detected in the serum of mice immunized with the JEV peptide by ELISA, CBA, and TBA. Moreover, mice immunized with the JEV peptide presented no abnormities related to anti-NMDAR antibodies according to western blotting, patch clamp, and a series of behavioral tests. In addition, active immunization with a recently reported GluN1 peptide failed to induce anti-NMDAR antibody production in mice. Conclusions: In this study, the attempt of active immunization with the JEV peptide to induce the production of anti-NMDAR antibodies via molecular mimicry failed. The pathogenesis of anti-NMDAR encephalitis following Japanese encephalitis remains to be elucidated

Systemic Cancer Therapy Does Not Significantly Impact Early Vaccine-Elicited SARS-CoV-2 Immunity in Patients with Solid Tumors

mRNA vaccines have been shown to be safe and effective in individuals with cancer. It is unclear, however, if systemic anti-cancer therapy impacts the coordinated cellular and humoral immune responses elicited by SARS-CoV-2 mRNA vaccines. To fill this knowledge gap, we assessed SARS-CoV-2 mRNA vaccine-elicited immunity in a cohort of patients with advanced solid tumors either under observation or receiving systemic anti-cancer therapy. This analysis revealed that SARS-CoV-2 mRNA vaccine-elicited cellular and humoral immunity was not significantly different in individuals with cancer receiving systemic anti-cancer therapy relative to individuals under observation. Furthermore, even though some patients exhibited suboptimal antibody titers after vaccination, SARS-CoV-2 specific cellular immune responses were still detected. These data suggest that antibody titers offer an incomplete picture of vaccine-elicited SARS-CoV-2 immunity in cancer patients undergoing active systemic anti-cancer therapy, and that vaccine-elicited cellular immunity exists even in the absence of significant quantities of SARS-CoV-2 specific antibodies