Annexin a2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and ebola virus infections

Zhengchen Su, Qing Chang, Aleksandra Drelich, Thomas Shelite, Barbara Judy, Yakun Liu, Jie Xiao, Changchen Zhou, Xi He, Yang Jin, Tais Saito, Shaojun Tang, Lynn Soong, Maki Wakamiya, Xiang Fang, Alexander Bukreyev, Thomas Ksiazek, William K. Russell, Bin Gong

Research output: Contribution to journalArticle

Abstract

Intracerebral microhemorrhages (CMHs) are small foci of hemorrhages in the cerebrum. Acute infections induced by some intracellular pathogens, including rickettsia, can result in CMHs. Annexin a2 (ANXA2) has been documented to play a functional role during intracellular bacterial adhesion. Here we report that ANXA2-knockout (KO) mice are more suscepti-ble to CMHs in response to rickettsia and Ebola virus infections, suggesting an essential role of ANXA2 in protecting vascular integrity during these intracellular pathogen infections. Proteomic analysis via mass spectrometry of whole brain lysates and brain-derived endo-somes from ANXA2-KO and wild-type (WT) mice post-infection with R. australis revealed that a variety of significant proteins were differentially expressed, and the follow-up function enrichment analysis had identified several relevant cell-cell junction functions. Immunohis-tology study confirmed that both infected WT and infected ANXA2-KO mice were subjected to adherens junctional protein (VE-cadherin) damages. However, key blood-brain barrier (BBB) components, tight junctional proteins ZO-1 and occludin, were disorganized in the brains from R. australis-infected ANXA2-KO mice, but not those of infected WT mice. Simi-lar ANXA2-KO dependent CMHs and fragments of ZO-1 and occludin were also observed in Ebola virus-infected ANXA2-KO mice, but not found in infected WT mice. Overall, our study revealed a novel role of ANXA2 in the formation of CMHs during R. australis and Ebola virus infections; and the underlying mechanism is relevant to the role of ANXA2-regu-lated tight junctions and its role in stabilizing the BBB in these deadly infections.

Original languageEnglish (US)
Article numbere0007960
Pages (from-to)1-30
Number of pages30
JournalPLoS neglected tropical diseases
Volume14
Issue number7
DOIs
StatePublished - Jul 2020

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

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