Biology subjects

Shah, A. H.

Publications and source records attributed to Shah, A. H..

3 recordsLinked to original sources

bioRxiv2026

Capsule types driving carbapenem-resistant Klebsiella pneumoniae in Pakistan are largely absent from the phage literature

Phage therapy is increasingly proposed for carbapenem-resistant Klebsiella pneumoniae, but most Klebsiella phages bind a single capsule type, so a phage is useful only where its capsule type circulates. We asked whether published phages cover the capsule types found in Pakistani patients. We typed 254 clinical K. pneumoniae genomes from Pakistan and curated the phage and depolymerase literature into 34 phage-capsule records covering 27 phages and 15 capsule types. Nearly half the cohort was unmatched: 121 of 254 isolates (47.6%), spanning 51 of 66 capsule types, belong to types for which no phage has been described, and 67 of those isolates carry a carbapenemase. Collapsing each BioProject to one isolate per type raises the unmatched fraction to 51.8%. To ask why, we typed 475 genomes sampled on identical criteria from India, Bangladesh and Nepal, China, Europe and the USA. Two capsule types separated sharply. KL81 accounted for 6.3% of South Asian genomes and none of 275 from China, Europe or the USA, and has no published phage; KL107 showed the reverse, 9.8% in those regions and absent from South Asia. Both survived collapsing (P = 0.0014 and P = 0.0002). Six further differences did not, and are attributable to clonal expansion within single studies. Phages are isolated against locally available hosts, so the capsule types entering the global phage collection track the regions doing the isolating. KL81 is a defined target for phage isolation in South Asia.

microbiology↗

bioRxiv2026

Targeting an RNA Editor to Impede H3K27M+ Pediatric Gliomas

Diffuse midline glioma (DMG) is a lethal pediatric brain tumor with no curative therapies. Immune checkpoint blockade (ICB) has shown limited efficacy in DMG, largely due to poor T cell infiltration, low immune checkpoint (IC) expression, and a low tumor mutational burden. Here, we identify adenosine deaminase acting on RNA (ADAR), an RNA-editing enzyme that suppresses endogenous dsRNA sensing, as a key mediator of immune evasion in H3K27M-mutant DMG. ADAR is significantly overexpressed in H3K27M tumors relative to wild-type high-grade gliomas, and its depletion selectively suppresses proliferation in patient-derived DMG cells. The H3K27M mutation was found to synergize with ADAR loss to increase retroelement expression, activate type I interferon signaling, and induce immune checkpoint expression. We further identify all-trans retinoic acid (ATRA) as a pharmacologic inducer of ADAR degradation. At clinically relevant doses, ATRA phenocopies ADAR depletion, enhancing antiviral and interferon responses while increasing tumor immunogenicity. In orthotopic immunocompetent DMG models, ATRA enhances CD8+ T cell infiltration and synergizes with ICB and irradiation to improve survival.

cancer biology↗

bioRxiv2024

Targeting ZNF638 activates antiviral immune responses and potentiates immune checkpoint inhibition in glioblastoma

Viral mimicry refers to the activation of innate anti-viral immune responses due to the induction of endogenous retroelement (RE) expression. Viral mimicry has been previously described to augment anti-tumor immune responses and sensitize solid tumors to immunotherapy including colorectal cancer, melanoma, and clear renal cell carcinoma. Here, we found that targeting a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression and poor immune cell infiltration (CD8+ T-cells, dendritic cells). ZNF638 knockdown decreased H3K9-trimethylation, increased cytosolic dsRNA and activated intracellular dsRNA-signaling cascades (RIG-I, MDA5 and IRF3). Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in patient-derived GBM neurospheres and diverse murine models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate interferon signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1 and perivascular CD8 cell infiltration, suggesting dsRNA-signaling may mediate response to immunotherapy. Finally, we showed that low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in rGBM patients and melanoma patients. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.

cancer biology↗