Biology subjects

Afkhami, S.

Publications and source records attributed to Afkhami, S..

6 recordsLinked to original sources

bioRxiv2025

Senataxin is required for optimal class switch recombination to the immunoglobulin A isotype

Senataxin (SETX) is an RNA/DNA helicase that plays a pivotal role in transcription, R-loop resolution, and the DNA damage response (DDR). Dysfunction of SETX, however, has been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis and ataxia with oculomotor apraxia type 2. Importantly, both R-loop resolution and the DDR are essential for class switch recombination (CSR) in B cells, a critical step in generating antibody diversity. Here we demonstrate that ex vivo polyclonal stimulation of SETX+/+ and SETX-/- mouse splenocytes results in equivalent amounts of IgM- and IgG-secreting B cells but significantly fewer IgA-producing B cells in SETX-/- mice. Additionally, SETX-/- mice generate significantly reduced antigen specific IgA titers following infection with influenza A virus. Sequencing of the IgA-secreting B cell repertoire revealed reduced clonal diversity in SETX-/- mice. SETX-/- mice also had increased R-loop formation within the IgA locus. Collectively, these data highlight an important role for SETX in mediating CSR to IgA. As such, a further understanding of SETXs role in the immune response is important for expanding our knowledge of both the general immunobiology relating to CSR as well as the immunological phenotypes associated with neurodegenerative diseases associate with mutations in SETX. One sentence summaryA deficiency in senataxin results in impaired class switching to IgA in vitro with decreased IgA response to infection and IgA repertoire diversity in vivo.

immunology↗

bioRxiv2024

Acute Viral Infection Accelerates Neurodegeneration in a Mouse Model of ALS

While several viral infections have been associated with amyotrophic lateral sclerosis (ALS), the mechanism(s) through which they promote disease has remained almost entirely elusive. This study investigated the impact of common, acute viral infections prior to disease onset on ALS progression in the SOD1G93A mouse model. A single sublethal infection prior to onset of ALS clinical signs was associated with markedly accelerated ALS disease progression characterized by rapid loss of hindlimb function. Prior infection resulted in gliosis in the lumbar spine and upregulation of transcriptional pathways involved in inflammatory responses, metabolic dysregulation, and muscular dysfunction. Therapeutic suppression of gliosis with an anti-inflammatory small molecule, or administration of a direct-acting antiviral, was associated with significantly improved ALS clinical signs, akin to what was observed in uninfected animals. This study provides causal and mechanistic evidence that the immune response elicited by acute viral infections may be an important etiological factor that alters ALS disease trajectory, and provides insight into novel therapeutic and preventative strategies for ALS. One Sentence SummaryAcute viral infection with influenza A virus and SARS-CoV-2 accelerates the progression of ALS in SOD1G93A mice.

immunology↗

bioRxiv2024

Respiratory mucosal administration of DNA aptamer nanomaterials protects against antigenically diverse SARS-CoV-2 variants

The ongoing COVID-19 pandemic has highlighted the need for innovative therapeutic strategies to combat rapidly evolving pathogens that challenge the efficacy of traditional vaccines and monoclonal antibody treatments. Here, we explored the potential of TMSA52, a previously described homotrimeric DNA aptamer as a universal prophylactic and therapeutic agent against SARS-CoV-2. TMSA52 demonstrates exceptional binding affinities and broad neutralization against diverse SARS-CoV-2 variant spike proteins that are further enhanced through multimerization onto lamellar iridium nanoplates. Respiratory mucosal delivery of TMSA52 nanomaterials was well-tolerated. Surprisingly, TMSA52 offered potent protection from infection with ancestral SARS-CoV-2 on-par with monoclonal antibodies, and superior protection against antigenically distant SARS-CoV-2 variants. These findings establish DNA aptamers as a promising, cost-effective, and scalable alternative to traditional monoclonal antibody therapies. This study underscores the potential of aptamer-based platforms as a next-generation strategy to enhance global pandemic preparedness and expand our arsenal of infectious disease countermeasures.

immunology↗

bioRxiv2022

Subcutaneous BCG vaccination protects against streptococcal pneumonia via regulating innate immune responses in the lung

Bacillus Calmette-Guerin (BCG) still remains the only licensed vaccine for TB and has been shown to provide nonspecific protection against unrelated pathogens. This has been attributed to the ability of BCG to modulate the innate immune system, known as trained innate immunity (TII). TII is associated with innate immune cells being in a hyper-responsive state leading to enhanced host defense against heterologous infections. Both epidemiological evidence and prospective studies demonstrate cutaneous BCG vaccine-induced TII provides enhanced innate protection against heterologous pathogens. Regardless of the extensive amounts of progress made thus far, the effect of cutaneous BCG vaccination against heterologous respiratory bacterial infections and the underlying mechanisms remain unknown. Here we show for the first time that s.c BCG vaccine-induced TII provides enhanced heterologous innate protection against pulmonary S. pneumoniae infection. We further demonstrate that this enhanced innate protection is mediated by accelerated neutrophilia in the lung and is independent of centrally trained circulating monocytes. New insight from this study will help design novel effective vaccination strategies against unrelated respiratory bacterial pathogens.

immunology↗

bioRxiv2021

Single-dose respiratory mucosal delivery of next-generation viral-vectored COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2

The emerging SARS-CoV-2 variants of concern (VOC) increasingly threaten the effectiveness of current first-generation COVID-19 vaccines that are administered intramuscularly and are designed to only target the spike protein. There is thus a pressing need to develop next-generation vaccine strategies to provide more broad and long-lasting protection. By using adenoviral vectors (Ad) of human and chimpanzee origin, we developed Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens and evaluated them following single-dose intramuscular or intranasal immunization in murine models. We show that respiratory mucosal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the three-arm immunity, consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. We further show that single-dose intranasal immunization provides robust protection against not only the ancestral strain of SARS-CoV-2, but also two emerging VOC, B.1.1.7 and B.1.351. Our findings indicate that single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC. This strategy has great potential to be used not only to boost first-generation vaccine-induced immunity but also to expand the breadth of protective T cell immunity at the respiratory mucosa.

immunology↗

bioRxiv2020

Early temporal dynamics of cellular responses to SARS-CoV-2

Type I interferons (IFNs) are our first line of defence against a virus. Protein over-expression studies have suggested the ability of SARS-CoV-2 proteins to block IFN responses. Emerging data also suggest that timing and extent of IFN production is associated with manifestation of COVID-19 severity. In spite of progress in understanding how SARS-CoV-2 activates antiviral responses, mechanistic studies into wildtype SARS-CoV-2-mediated induction and inhibition of human type I IFN responses are lacking. Here we demonstrate that SARS-CoV-2 infection induces a mild type I IFN response in vitro and in moderate cases of COVID-19. In vitro stimulation of type I IFN expression and signaling in human airway epithelial cells is associated with activation of canonical transcriptions factors, and SARS-CoV-2 is unable to inhibit exogenous induction of these responses. Our data demonstrate that SARS-CoV-2 is not adept in blocking type I IFN responses and provide support for ongoing IFN clinical trials. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/158154v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@193c540org.highwire.dtl.DTLVardef@7b106forg.highwire.dtl.DTLVardef@1741cfforg.highwire.dtl.DTLVardef@1bde68_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL SUMMARY C_FIG

immunology↗