Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

Su, Zhengchen; Chang, Qing; Drelich, Aleksandra; Shelite, Thomas R.; Judy, Barbara M.; Liu, Yakun; Xiao, Jie; Zhou, Changchen; He, Xi; Jin, Yang; Saito, Taís B.; Tang, Shao-Jun; Soong, Lynn; Wakamiya, Maki; Fang, Xiang; Bukreyev, Alexander; Ksiazek, Thomas G.; Russell, William K.; Gong, Bin

doi:10.1371/journal.pntd.0007960

Cited by 11 publications

(9 citation statements)

References 130 publications

(160 reference statements)

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“…In a murine model of intravenous inoculation of R. parkeri (Atlantic Rainforest strain) using C3H/HeN mice, signs of illness begin on day 3 and fatalities occur on day 6 p.i. ( 95), during which time microvascular damage is detected in multiple organs (95); this is similar to the pathology observed in our murine model of R. australis infection (85,87). However, differences among various pathogen species must be considered in future mechanistic studies.…”

Section: Discussionsupporting

confidence: 77%

“…Using SEC, we isolated small EVs (50 to 150 nm) from rickettsia-infected mouse plasma and HUVECs from culture media; both were passed through two 0.2-mm filters. Quantitative real-time PCR validated that no rickettsial DNA copies were detected in either R-plsExos isolated from R. australis-or R. parkeri-infected mice infected with 2 50% lethal doses (LD 50 ) of bacteria (80,(84)(85)(86)(87) on day 4 postinfection (p.i.) or the R-ECExos that were purified 72 h p.i.…”

Section: Resultsmentioning

confidence: 95%

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Endothelial Exosome Plays a Functional Role during Rickettsial Infection

Liu

Zhou

et al. 2021

mBio

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Spotted fever group rickettsioses (SFRs) are devastating human infections. Vascular endothelial cells (ECs) are the primary targets of rickettsial infection. Edema resulting from EC barrier dysfunction occurs in the brain and lungs in most cases of lethal SFR, but the underlying mechanisms remain unclear. The aim of the study was to explore the potential role of Rickettsia-infected, EC-derived exosomes (Exos) during infection. Using size exclusion chromatography (SEC), we purified Exos from conditioned, filtered, bacterium-free media collected from Rickettsia parkeri-infected human umbilical vein ECs (HUVECs) (R-ECExos) and plasma of Rickettsia australis- or R. parkeri-infected mice (R-plsExos). We observed that rickettsial infection increased the release of heterogeneous plsExos, but endothelial exosomal size, morphology, and production were not significantly altered following infection. Compared to normal plsExos and ECExos, both R-plsExos and R-ECExos induced dysfunction of recipient normal brain microvascular ECs (BMECs). The effect of R-plsExos on mouse recipient BMEC barrier function is dose dependent. The effect of R-ECExos on human recipient BMEC barrier function is dependent on the exosomal RNA cargo. Next-generation sequencing analysis and stem-loop quantitative reverse transcription-PCR (RT-qPCR) validation revealed that rickettsial infection triggered the selective enrichment of endothelial exosomal mir-23a and mir-30b, which potentially target the endothelial barrier. To our knowledge, this is the first report on the functional role of extracellular vesicles following infection by obligately intracellular bacteria. IMPORTANCE Spotted fever group rickettsioses are devastating human infections. Vascular endothelial cells are the primary targets of infection. Edema resulting from endothelial barrier dysfunction occurs in the brain and lungs in most cases of lethal rickettsioses, but the underlying mechanisms remain unclear. The aim of the study was to explore the potential role of Rickettsia-infected, endothelial cell-derived exosomes during infection. We observed that rickettsial infection increased the release of heterogeneous plasma Exos, but endothelial exosomal size, morphology, and production were not significantly altered following infection. Rickettsia-infected, endothelial cell-derived exosomes induced dysfunction of human recipient normal brain microvascular endothelial cells. The effect is dependent on the exosomal RNA cargo. Next-generation sequencing analysis revealed that rickettsial infection triggered the selective enrichment of endothelial exosomal mir-23a and mir-30b, which potentially target the endothelial barrier. To our knowledge, this is the first report on the functional role of extracellular vesicles following infection by obligately intracellular bacteria.

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Section: Discussionsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 95%

Endothelial Exosome Plays a Functional Role during Rickettsial Infection

Liu

Zhou

et al. 2021

mBio

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“…Sucrose cushion-purified SARS-CoV-2 virion samples were prepared for LC-MS/MS analysis as previously described ( 28 ). Samples were analyzed by nanoLC-MS/MS (nanoRSLC, ThermoFisher) using an Aurora series (Ion Opticks) reversed phase high-performance liquid chromatography column (25 cm length × 75 µm inner diameter) directly injected to an Orbitrap Eclipse using a 120 min gradient (mobile phase A = 0.1% formic acid (Thermo Fisher), mobile phase B = 99.9% acetonitrile with 0.1% formic acid (Thermo Fisher); hold 12% B for 5 min, 2 to 6% B in 0.1 min, 6 to 25% in 100 min, 25 to 50% in 15 min) at a flow rate of 350 nL/min.…”

Section: Methodsmentioning

confidence: 99%

QTQTN motif upstream of the furin-cleavage site plays a key role in SARS-CoV-2 infection and pathogenesis

Lokugamage

Plante

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The furin cleavage site (FCS), an unusual feature in the SARS-CoV-2 spike protein, has been spotlighted as a factor key to facilitating infection and pathogenesis by increasing spike processing. Similarly, the QTQTN motif directly upstream of the FCS is also an unusual feature for group 2B coronaviruses (CoVs). The QTQTN deletion has consistently been observed in in vitro cultured virus stocks and some clinical isolates. To determine whether the QTQTN motif is critical to SARS-CoV-2 replication and pathogenesis, we generated a mutant deleting the QTQTN motif (ΔQTQTN). Here, we report that the QTQTN deletion attenuates viral replication in respiratory cells in vitro and attenuates disease in vivo. The deletion results in a shortened, more rigid peptide loop that contains the FCS and is less accessible to host proteases, such as TMPRSS2. Thus, the deletion reduced the efficiency of spike processing and attenuates SARS-CoV-2 infection. Importantly, the QTQTN motif also contains residues that are glycosylated, and disruption of its glycosylation also attenuates virus replication in a TMPRSS2-dependent manner. Together, our results reveal that three aspects of the S1/S2 cleavage site—the FCS, loop length, and glycosylation—are required for efficient SARS-CoV-2 replication and pathogenesis.

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“…Immunoprecipitated UNC-45-mNG samples were prepared for LC-MS/MS analysis as previously described (Su et al, 2020). Samples were analyzed by nanoLC-MS/MS (nanoRSLC, ThermoFisher) using an Aurora series (Ion Opticks) reversed phase HPLC column (25 cm length × 75 µm inner diameter) directly injected to an Orbitrap Eclipse using a 120 min gradient (mobile phase A = 0.1% formic acid (Thermo Fisher), mobile phase B = 99.9% acetonitrile with 0.1% formic acid (Thermo Fisher); hold 12% B for 5 min, 2-6% B in 0.1 min, 6-25% in 100 min, 25-50% in 15 min) at a flow rate of 350 nL/min.…”

Section: Methodsmentioning

confidence: 99%

UNC-45 has a crucial role in maintaining muscle sarcomeres during aging in Caenorhabditis elegans

Matheny

Qadota

Kimelman

et al. 2022

Preprint

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As people live longer, age-related diseases, like sarcopenia, will become a greater public health concern. We use the model organism C. elegans to better understand the molecular mechanisms behind muscle maintenance. Muscle function is dependent on having properly organized and functioning thick filaments, which are primarily composed of myosin. The myosin head requires the chaperone UNC-45 to initially fold it after translation and is likely used to re-fold back to functionality after thermal or chemical stress induced unfolding. We observe an early onset of sarcopeania when UNC-45 is perturbed during adulthood. We observe that during adult aging, there is a sequential decline of HSP-90, UNC-45, and then myosin. Myosin and UNC-45 protein decline are independent of steady state mRNA levels. Loss of UNC-45 is correlated with an increase in phosphorylation of the protein. By mass spectrometry, S111 was identified as being phosphorylated and this modification may affect binding to HSP-90. A longevity mutant with delayed onset of sarcopenia also shows a delay in the loss of HSP-90, UNC-45, and myosin. We also see a decrease in UNC-45 protein, but not transcript, in an hsp-90 loss of function mutant, suggesting a role for HSP-90 in stabilizing UNC-45. This leads us to propose the model that during aging, a loss of HSP-90 leads to UNC-45 being post translationally modified, such as phosphorylation, and degraded, which then leads to a loss of myosin, and thus muscle mass and function. A better understanding of how myosin and its chaperone proteins are regulated and affected by aging will lead to better preventative care and treatment of sarcopenia and, possibly, the age-related decline of heart muscle function.

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Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

Cited by 11 publications

References 130 publications

Endothelial Exosome Plays a Functional Role during Rickettsial Infection

Endothelial Exosome Plays a Functional Role during Rickettsial Infection

QTQTN motif upstream of the furin-cleavage site plays a key role in SARS-CoV-2 infection and pathogenesis

UNC-45 has a crucial role in maintaining muscle sarcomeres during aging in Caenorhabditis elegans

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