Biology subjects

Khil, P. P.

Publications and source records attributed to Khil, P. P..

3 recordsLinked to original sources

bioRxiv2026

Antibody Profiles in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is characterized by prepubertal abrupt onset of obsessive-compulsive disorder (OCD). The sine qua non is group A streptococcus (GAS) infection, which is hypothesized to elicit an IgG-class anti-GAS antibody response that cross-reacts with antigens in the basal ganglia. However, the association between GAS antibody (GAS-IgG) levels and PANDAS has been inconsistent, and qualitative differences in GAS-IgG profiles have not been carefully evaluated in well-phenotyped cohorts. Moreover, independent studies have yet to converge on anti-neural autoantibodies that are specific to PANDAS. Here, we used phage display immunoprecipitation sequencing (PhIP-Seq) to perform ultra-deep anti-pathogen antibody repertoire profiling of serum from definitive pediatric PANDAS patients (N = 34) collected as part of a prior double-blind, placebo-controlled clinical trial of intravenous immunoglobulin (IVIg). PANDAS cases were compared to pediatric controls without a history of neuropsychiatric illness (N = 31). To assess for objective evidence of neuroglial injury, serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) levels were compared to healthy pediatric controls. Within PANDAS, NfL and GFAP levels were compared between pre- and post-treatment sera. To evaluate for central autoantibodies, a subset of baseline cerebrospinal fluid (CSF) samples (N = 25) was profiled by full-length human protein microarray. Though GAS reactivity by PhIP-Seq was well correlated with clinical anti-DNaseB and anti-streptolysin O titers, there were no quantitative or qualitative differences in GAS-IgG profiles between PANDAS and controls. Furthermore, NfL and GFAP levels did not differ between cases and controls. Within PANDAS, changes in NfL or GFAP levels at six weeks did not differ between placebo and IVIg groups. However, CSF autoantibody profiling by protein microarray revealed infrequent but notable candidate autoantibodies. In one patient, we identified autoantibodies against Argonaute family proteins (AGO-IgG), a marker of autoimmune sensory neuropathy. Longitudinal measurement of AGO-IgG in sera revealed that titers were unchanged after placebo, but decreased after IVIg, coinciding with symptomatic improvement, including a decrease in that patients CY-BOCS score. Overall, these results do not support an etiologic role for GAS-IgG in PANDAS. However, some individuals diagnosed with PANDAS may harbor anti-neural autoantibodies.

immunology↗

bioRxiv2023

The Host Adapted Fungal Pathogens of Pneumocystis Genus Utilize Genic Regional Centromeres

Centromeres are constricted chromosomal regions that are essential for cell division. In eukaryotes, centromeres display a remarkable architectural and genetic diversity. The basis of centromere accelerated evolution remains elusive. Here we focused on Pneumocystis species, a group of Mammalian-specific fungal pathogens that form a sister taxon with that of the Schizosaccharomyces pombe, an important genetic model for centromere biology research. Methods allowing reliable continuous culture of Pneumocystis species do not currently exist, precluding genetic manipulation. CENP-A, a variant of histone H3, is the epigenetic marker that defines centromeres in most eukaryotes. Using heterologous complementation, we show that the Pneumocystis CENP-A ortholog is functionally equivalent to CENP-ACnp1 of Schizosaccharomyces pombe. Using organisms from a short-term in vitro culture or infected animal models and ChIP-Seq, we identified CENP-A bound regions in two Pneumocystis species that diverged [~]35 million years ago. Each species has a unique short regional centromere (< 10kb) flanked by heterochromatin in 16-17 monocentric chromosomes. They span active genes and lack conserved DNA sequence motifs and repeats. These features suggest an epigenetic specification of centromere function. Analysis of centromeric DNA across multiple Pneumocystis species suggest a vertical transmission at least 100 million years ago. Common ancestry of Pneumocystis and S. pombe centromeres is untraceable at the DNA level but the overall architectural similarity could be the result of functional constraint for successful chromosomal segregation. Significance StatementPneumocystis species offer a suitable genetic system to study centromere evolution in pathogens because of their phylogenetic proximity with the nonpathogenic yeast Schizosaccharomyces pombe, a popular model for cell biology. We used this system to explore how centromeres have evolved after divergence of the two clades [~]460 million years ago. To address this question, we established a protocol combining short-term culture and ChIP-Seq to characterize centromeres in multiple Pneumocystis species. We show that Pneumocystis have short epigenetic centromeres that function differently from those in S. pombe. One sentence summaryInsights into the formation of genic centromeres in fungal pathogens.

genomics↗

bioRxiv2020

Genomic insights into the host specific adaptation of the Pneumocystis genus and emergence of the human pathogen Pneumocystis jirovecii

Pneumocystis jirovecii, the fungal agent of human Pneumocystis pneumonia, is closely related to macaque Pneumocystis. Little is known about other Pneumocystis species in distantly related mammals, none of which are capable of establishing infection in humans. The molecular basis of host specificity in Pneumocystis remains unknown as experiments are limited due to an inability to culture any species in vitro. To explore Pneumocystis evolutionary adaptations, we have sequenced the genomes of species infecting macaques, rabbits, dogs and rats and compared them to available genomes of species infecting humans, mice and rats. Complete whole genome sequence data enables analysis and robust phylogeny, identification of important genetic features of the host adaptation, and estimation of speciation timing relative to the rise of their mammalian hosts. Our data reveals novel insights into the evolution of P. jirovecii, the sole member of the genus able to infect humans.

evolutionary biology↗