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Limited proteolysis of SARS-CoV-2 Spike treated at pH 2 or pH 7

ABSTRACT: SARS-CoV-2 is a respiratory virus spreading via aerosol particles. Aerosol particles can exhibit extreme environmental conditions affecting contained viruses, including acidic pH. Here, we study how harsh pH conditions, such as pH 2, can affect the structure of Spike, which is the main protein mediating viral entry into host cells. By performing limited proteolysis with the unspecific protease K coupled to mass spectrometry, we identified 4 semi-tryptic peptides in the S2 subdomain of spike. These results indicate structural changes in the S2 subdomain induced by treatment at pH 2.

INSTRUMENT(S): ACQUITY UPLC, Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human) Severe Acute Respiratory Syndrome Coronavirus 2

SUBMITTER: Irina Glas

LAB HEAD: Silke Stertz

PROVIDER: PXD064612 | Pride | 2025-07-17

REPOSITORIES: Pride

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			Action	DRS
	20250516_002_S944635_pH2_PK_rep1.raw	Raw
	20250516_003_S944639_pH7_PK_rep1.raw	Raw
	20250516_004_S944640_pH7_PK_rep2.raw	Raw
	20250516_005_S944638_pH2_PK_rep4.raw	Raw
	20250516_007_S944641_pH7_PK_rep3.raw	Raw

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Project description:Multiple respiratory viruses including Influenza A virus (IAV) can be transmitted via expiratory aerosol particles, and many studies have established that environmental conditions can affect viral infectivity during airborne transmission. Low aerosol pH was recently identified as a major factor influencing the infectivity of aerosol-borne IAV and SARS-CoV-2, however, there is a fundamental lack of understanding as to the mechanisms leading to viral inactivation within the acidic aerosol micro-environment. Here, we identified that the early stages of the IAV infection cycle were impacted by transient exposure to acidic aerosol conditions (pH below 5.5), which was primarily attributed to loss of binding function of the viral protein haemagglutinin. Viral capsid integrity was also somewhat affected by transient acidic exposure. We then characterised the structural changes associated with loss of viral infectivity using whole-virus hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), and observed discrete regions of unfolding in the external viral protein haemagglutinin and in the internal matrix protein 1. Viral nucleoprotein structure appeared to be unaffected by exposure to acidic aerosol conditions, and no changes to viral genome integrity or to lipids within the viral envelope were detected using our whole-virus methods. Collectively, these data indicate that viral inactivation observed under indoor aerosol conditions is mediated by specific protein conformational changes, particularly to haemagglutinin. This study additionally provides a proof-of-concept that HDX-MS is a highly effective method for characterisation of internal and external proteins of whole enveloped viruses such as IAV. Overall, improved understanding of the fate of respiratory viruses within exhaled aerosols will aid the development of novel strategies and therapeutics to control the severity of seasonal and/or pandemic influenza, and constitutes a global public health priority.

Project description:We aim to compare the genomic discrepancies across de novo Ph+ ALL, Ph+ MPAL and Ph+ AML, three diseases characterized by the occurrence of BCR-ABL1 transcripts but showing varied immunophenotypes. The data we are now submitting is the genomic copy number variants of these three groups. The following is the abstract with associated manuscript. The chromosome abnormality of Philadelphia (Ph) is typically seen in de novo acute lymphoblastic leukemia (ALL). It has also been identified in mixed phenotype acute leukemia (MPAL) and acute myeloid leukemia (AML) in the revisions to World Health Organization classification of myeloid neoplasms and actue leukemia. The discrepancies between these patients and potential mechanisms underlying differentiation fate of the leukemia cells remain poorly defined. We evaluated the clinical, genomic and transcriptomic features of Ph+ ALL, Ph+ MPAL and Ph+ AML by taking advantage of high-density genomic analysis, including next-generation sequencing array comparative genomic hybridization and gene expression profiling for transcriptomic analysis. Our results showed that the three cohorts demonstrated diversified clinical features. Ph+ ALL had the best response to induction therapy, with a complete remission (CR) rate of 93.5 and molecular response of 43.5%. Ph+ MPAL had a 90.0% CR rate but only 5.9% of molecular response. The CR rate of Ph+ AML was only 68.8%. Ph+ ALL was characterized by loss and mutations of B-cell development gene IKZF1 and PAX5, and frequent histone H3K36 trimethyltransferase SETD2 mutations. SETD2 mutations were detected in 11.3% of Ph+ ALL patients and predicted higher relapse rate. Ph+ MPAL and Ph+ AML featured high frequency of RUNX1 mutations. Further studies showed RUNX1-R177X mutation inhibited 32D cell differentiation induced by G-Csf, and cooperated with BCR-ABL1 to lead to myeloid differentiation arrest of human cord blood CD34+ cells. It is therefore presumed that these additional mutations work in synergy with BCR-ABL1 fusion gene to facilitate the development of Ph-positive acute leukemia in different immunophenotypic classifications.

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Limited proteolysis of SARS-CoV-2 Spike treated at pH 2 or pH 7

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