Nosocomial Pneumonia Elicits an Endothelial Proteinopathy: Evidence for a Source of Neurotoxic Amyloids in Critically Ill Patients

Lin, Mike T.; Balczon, Ron; Pittet, Jean–François; Wagener, Brant M.; Moser, Stephen A.; Morrow, K. Adam; Voth, S.B.; Francis, C.M.; Leavesley, Silas J.; Bell, Jessica; Alvarez, Diego F.; Stevens, Troy

doi:10.1164/rccm.201801-0060le

Cited by 23 publications

(82 citation statements)

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“…We previously reported that infection elicits the endothelial production of cytotoxic amyloids (22,53), which can be detected in the BALF of pneumonia patients. Neutralizing these amyloids alleviates cerebral endothelial disruption and rescues synaptic plasticity (23). Here, we report that endothelium-derived amyloids within the CSF impair working memory and performance in hippocampaldependent and -independent tasks.…”

Section: Discussionmentioning

confidence: 79%

“…Amyloids within the A11-eluate did not consistently affect either the pre-or the postsynaptic response. Notably, our previous studies have shown that the same CSF samples inhibit LTP (23). Taken together, results from CSF studies suggest that bacterial species and virulence capacity and patient heterogeneity are all key components to our understanding of pneumonia-elicited brain impairment and the pre-and postsynaptic responses are not the sole determinants of LTP and learning (48-52) ( Fig.…”

Section: Nosocomial Pneumonia Elicits Endothelial Amyloid and Tau Promentioning

confidence: 79%

“…6H), although both cytotoxins were equally potent in LTP abolishment. In studies Results were obtained using endothelium-derived amyloids and CSF amyloids in bacterial pneumonia patients with or without antibody immunodepletion (23). The treatment that induces synaptic neurotoxicity in bathed hippocampal slices:indicates there was no effect of the treatment; + indicates the designated response was impaired; and +/2 indicates heterogeneity among patients and bacterial strains, presence of different amyloid species in the CSF, or both.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 6 patients (BALF-positive and -negative) suffered a traumatic or vascular brain injury that precipitated placement of an external ventricular drain, and 1 patient had ventriculoperitoneal shunt failure. CSF used in this study was from the same patient cohort previously studied, in which we examined long-term potentiation (LTP) (23).…”

Section: Patient Enrollment and Collection Of Csfmentioning

confidence: 99%

“…We recently showed that the Pseudomonas aeruginosa type III secretion system (T3SS) and exoenzyme effectors acutely induce pulmonary endothelial production and release of cytotoxic amyloid and tau proteins into the airways and blood of ICU patients (19)(20)(21)(22). The cytotoxins are detectable in the bronchoalveolar lavage fluid (BALF), plasma, and cerebrospinal fluid (CSF) of patients who tested positive for monomicrobial nosocomial pneumonia (23), suggesting that lung-derived amyloids could injure brain function. Importantly, these amyloids share features of prions; they ABBREVIATIONS: Ab, amyloid b; ACSF, artificial CSF; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BALF, bronchoalveolar lavage fluid; CFU, colony-forming unit; CSF, cerebrospinal fluid; FV, fiber volley; ICU, intensive care unit; ICV, intracerebroventricular; LTP, longterm potentiation; NMDA, N-methyl-D-aspartate; PA103, Pseudomonas aeruginosa isolated from patient 103; DPcrV, mutant strain of P. aeruginosa lacking a functional type 3 secretion system needle tip complex; Q1, quadrant 1; T3SS, type III secretion system are heat stable, RNase and DNase insensitive, protease resistant, transmissible, and self-replicating (22).…”

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Infection‐induced endothelial amyloids impair memory

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Patients with nosocomial pneumonia exhibit elevated levels of neurotoxic amyloid and tau proteins in the cerebrospinal fluid (CSF). In vitro studies indicate that pulmonary endothelium infected with clinical isolates of either Pseudomonas aeruginosa, Klebsiella pneumoniae, or Staphylococcus aureus produces and releases cytotoxic amyloid and tau proteins. However, the effects of the pulmonary endothelium‐derived amyloid and tau proteins on brain function have not been elucidated. Here, we show that P. aeruginosa infection elicits accumulation of detergent insoluble tau protein in the mouse brain and inhibits synaptic plasticity. Mice receiving endothelium‐derived amyloid and tau proteins via intracerebroventricular injection exhibit a learning and memory deficit in object recognition, fear conditioning, and Morris water maze studies. We compared endothelial supernatants obtained after the endothelia were infected with P. aeruginosa possessing an intact [P. aeruginosa isolated from patient 103 (PA103) supernatant] or defective [mutant strain of P. aeruginosa lacking a functional type 3 secretion system needle tip complex (ΔPcrV) supernatant] type 3 secretion system. Whereas the PA103 supernatant impaired working memory, the ΔPcrV supernatant had no effect. Immunodepleting amyloid or tau proteins from the PA103 supernatant with the A11 or T22 antibodies, respectively, overtly rescued working memory. Recordings from hippocampal slices treated with endothelial supernatants or CSF from patients with or without nosocomial pneumonia indicated that endothelium‐derived neurotoxins disrupted the postsynaptic synaptic response. Taken together, these results establish a plausible mechanism for the neurologic sequelae consequent to nosocomial bacterial pneumonia.—Balczon, R., Pittet, J.‐F., Wagener, B. M., Moser, S. A., Voth, S., Vorhees, C. V., Williams, M. T., Bridges, J. P., Alvarez, D. F., Koloteva, A., Xu, Y., Zha, X.‐M., Audia, J. P., Stevens, T., Lin, M. T. Infection‐induced endothelial amyloids impair memory. FASEB J. 33, 10300–10314 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 79%

Section: Nosocomial Pneumonia Elicits Endothelial Amyloid and Tau Promentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Patient Enrollment and Collection Of Csfmentioning

confidence: 99%

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confidence: 99%

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Infection‐induced endothelial amyloids impair memory

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Cystatin C regulates the cytotoxicity of infection‐induced endothelial‐derived β‐amyloid

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Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy

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et al. 2022

Journal of Biological Chemistry

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Nosocomial Pneumonia Elicits an Endothelial Proteinopathy: Evidence for a Source of Neurotoxic Amyloids in Critically Ill Patients

Cited by 23 publications

References 10 publications

Infection‐induced endothelial amyloids impair memory

Infection‐induced endothelial amyloids impair memory

Cystatin C regulates the cytotoxicity of infection‐induced endothelial‐derived β‐amyloid

Cytotoxic tau released from lung microvascular endothelial cells upon infection with Pseudomonas aeruginosa promotes neuronal tauopathy

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