Perspectives on the Intracellular Bacterium Chlamydia pneumoniae in Late-Onset Dementia

Purpose of Review Chronic diseases remain a daunting challenge for clinicians and researchers alike. While difficult to completely understand, most chronic diseases, including late-onset dementias, are thought to arise as an interplay between host genetic factors and environmental insults. One of the most diverse and ubiquitous environmental insults centers on infectious agents. Associations of infectious agents with late-onset dementia have taken on heightened importance, including our investigations of infection by the intracellular respiratory bacterium, Chlamydia pneumoniae (Cpn), in late-onset dementia of the Alzheimer’s type. Recent Findings Over the last two decades, the relationship of this infection to pathogenesis in late-onset dementia has become much clearer. This clarity has resulted from applying contemporary molecular genetic, biochemical, immunochemical, and cell culture techniques to analysis of human brains, animal models, and relevant in vitro cell culture systems. Data from these studies, taken in aggregate form, now can be applied to evaluation of proof of concept for causation of this infection with late-onset disease. In this evaluation, modifications to the original Koch postulates can be useful for elucidating causation. Summary All such relevant studies are outlined and summarized in this review, and they demonstrate the utility of applying modified Koch postulates to the etiology of late-onset dementia of the Alzheimer’s type. Regardless, it is clear that even with strong observational evidence, in combination with application of modifications of Koch’s postulates, we will not be able to conclusively state that Cpn infection is causative for disease pathogenesis in late-onset dementia. Moreover, this conclusion obtains as well for the putative causation of this condition by other pathogens, including herpes simplex virus type 1, Borrelia burgdorferi, and Porphyromonas gingivalis

Emerging Microbial and Viral Infections of the Central Nervous System

This review focuses on emerging viral and bacterial infections in the human central nervous system (CNS) that are responsible for significant global morbidity and mortality. These infections include those responsible for acute neurological disease such as meningitis and encephalitis as well those associated with chronic neurodegenerative conditions. Recent changes in climate conditions and pollution have been precipitating factors leading to the emergence of many of these pathogenic organisms. In addition, increased urbanization, global travel, life span, and exposure to new vectors have promoted the organisms’ spread across the globe. Categorization of many of these organisms includes identification of new species, recognition of new tropism to the CNS, spread into naïve demographic areas, increased human contact with zoonotic repositories including insect vectors, and reemergence of well-known organisms. These mechanisms are highlighted for the different organisms included in this review. Other mechanisms for CNS emergence such as genetic mutation of the organisms and immunosuppression and/or immunosenescence of the host are addressed. Viral and bacterial infections in chronic neurodegenerative diseases traditionally not thought to be infectious are considered. Although this review cannot be all-inclusive, the organisms included represent a sampling of extremely important microbes and their role in CNS pathogenesis in the twenty-first century

Editorial: Infection, inflammation, and neurodegeneration: A critical path to Alzheimer\u27s disease, Volume II.

No abstract availabl

Herpes simplex virus type 1 and Chlamydia pneumoniae infection of astrocytes: the effects of co-infection on pathogen replication

Background: Chlamydia pneumoniae (Cpn) and Herpes simplex virus type 1 (HSV-1) have been studied as pathogens contributing to neurodegenerative diseases. Cpn and HSV-1 are both ubiquitous, thus many individuals presumably are exposed to both pathogens during their life time. Since Cpn can establish persistence under adverse environmental conditions, we speculate that productive HSV infection might induce Cpn persistence in cells infected with both pathogens. Intermittent reactivation of either or both pathogens might contribute to progressive pathology associated with neurodegenerative diseases. Objectives: Determine whether Cpn and HSV-1 can co-infect cells and whether the presence of one pathogen alters replication of the other. Methods: The ability of Cpn and HSV-1 to co-infect an astrocyte cell line (STTG-1) was analyzed by immunofluorescence (IF) labeling using antibodies specific for HSV and Cpn, and RT-PCR using primers specific for each pathogen. Cells were infected with HSV or Cpn alone, or co infected with both pathogens for 24 or 48 hours. Results: IF revealed that cells could be simultaneously infected with both pathogens. Gene expression data support the observation that HSV replication is somewhat diminished in the presence of Cpn; similarly, the developmental cycle of Cpn appears to be disrupted by HSV. Conclusions: IF and gene expression data suggest both HSV-1 and Cpn inhibit, but do not prevent, infection by the second pathogen, possibly by competing for the same cellular receptors. Moreover, disruption of host cell transcription by HSV-1 may modify normal Cpn developmen

Chlamydia pneumoniae Infection of Monocytes in vitro Stimulates Innate and Adaptive Immune Responses Relevant to those in Alzheimer\u27s Disease.

Background: Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder in which infection with Chlamydia pneumoniae (Cpn) has been associated. Cpn is an obligate intracellular respiratory pathogen that may enter the central nervous system (CNS) following infection and trafficking of monocytes through the blood-brain barrier. Following this entry, these cells may secrete pro-inflammatory cytokines and chemokines that have been identified in the AD brain, which have been thought to contribute to AD neurodegeneration. The objectives of this work were: (i) to determine if Cpn infection influences monocyte gene transcript expression at 48 hours post-infection and (ii) to analyze whether pro-inflammatory cytokines are produced and secreted from these cells over 24 to 120 hours post-infection. Methods: Gene transcription was analyzed by RT-PCR using an innate and adaptive immunity microarray with 84 genes organized into 5 functional categories: inflammatory response, host defense against bacteria, antibacterial humoral response, septic shock, and cytokines, chemokines and their receptors. Statistical analysis of the results was performed using the Student\u27s t-test. P-values ≤ 0.05 were considered to be significant. ELISA was performed on supernatants from uninfected and Cpn-infected THP1 monocytes followed by statistical analysis with ANOVA. Results: When Cpn-infected THP1 human monocytes were compared to control uninfected monocytes at 48 hours post-infection, 17 genes were found to have a significant 4-fold or greater expression, and no gene expression was found to be down-regulated. Furthermore, cytokine secretion (IL-1ß, IL-6, IL-8) appears to be maintained for an extended period of infection. Conclusions: Utilizing RT-PCR and ELISA techniques, our data demonstrate that Cpn infection of THP1 human monocytes promotes an innate immune response and suggests a potential role in the initiation of inflammation in sporadic/late-onset Alzheimer\u27s disease

Evaluation of Smell and miRNA Biomarkers in Alzheimer’s Disease (AD)

Abstract and poster under embargo until May 31, 2019

Role of Microbes in the Development of Alzheimer\u27s Disease: State of the Art - An International Symposium Presented at the 2017 IAGG Congress in San Francisco.

This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer\u27s disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by th

Chlamydophila (Chlamydia) pneumoniae promotes Ab 1-42 amyloid processing in Neuronal Cells: A Pathogenic Trigger for Alzheimer\u27s Disease

Background: Previously, our laboratory identified Chlamydophila (Chlamydia) pneumoniae (Cpn) in autopsied sporadic AD brains. Furthermore, we have developed a BALB/c mouse model that demonstrated infection-induced amyloid plaques similar to those found in AD, and demonstrated that Cpn infection of neuronal cells inhibited apoptotic pathways of cell death. Hypothesis: Our current studies address whether infection with Cpn in neuronal cells triggers abnormal cleavage of the beta amyloid precursor protein (bAPP) into Ab1-42, thereby contributing to amyloid plaque formation characteristic of the pathology identified in AD. Materials and Methods: Human neuroblastoma cells were infected with the respiratory strain AR39 Cpn in vitro, then amyloid processing was analyzed and quantitated using immunocytochemistry, Western blotting and ELISA assays. Results: Cpn was shown to infect neuronal cells and induce intracellular amyloid processing. Cpn infection yielded cytoplasmic labeling of Ab 1-42 that was increased relative to uninfected cells. The ELISA assay revealed that in neuronal cell lysates, Ab 1-42 in the infected cells was increased 3 to 16-fold over the uninfected cells, from 24 to 72hr post infection. Western blot analysis confirmed an increase in Ab 1-42 in the infected neuronal cell lysates. Conclusions: These data suggest that infection of neuronal cells with Chlamydophila (Chlamydia) pneumoniae alters the processing of bAPP, thereby producing Ab1-42. Therefore, these studies and previous research reported by our laboratory support the implication of Cpn as a pathogenic agent in perpetuating the hallmark amyloid plaque formations observed in AD. This concept holds major therapeutic considerations for future studies.https://digitalcommons.pcom.edu/posters/1004/thumbnail.jp

Assessment of the impact of race and proxies of socioeconomic status on the prevalence and health outcome of peripartum cardiomyopathy (PPCM) using the “All of Us” Databank

Background: Peripartum Cardiomyopathy (PPCM) is a form of cardiomyopathy occurring during the last month of pregnancy or within months after giving birth in women with previously normal hearts. PPCM is an idiopathic systolic dysfunction that causes a reduced left ventricle ejection fraction. The estimated incidence of PPCM worldwide is 1 diagnosis out of 2,000 live births, and the causes of PPCM remain unknown. A retrospective cohort study conducted at the University of Pennsylvania Health System by Getz et al. showed that black race and socioeconomic proxies (like neighborhood disadvantage index (NDI)) were independently associated with sustained cardiac dysfunction (Getz et al., Am Heart J 2021). This study also showed that from all the components of NDI (education, high rental occupied housing, annual income below poverty line, female headed household, adults unemployed, adults on public assistance), low education and high rental occupied housing were significantly associated with sustained cardiac dysfunction. The central aim of the present project is to assess the effect of socioeconomic proxies (including NDI, lack of access to health care and food insecurity) on the prevalence of sustained cardiac dysfunction from PPCM across the US using the “All of Us” databank. A secondary aim is to test the compliance of the All of Us database capacity to interrogate this potential association. Lastly, we aim to compare the results obtained from the All of Us database with the UK Biobank. Methods: The All of Us databank (Ramirez et al., Patterns 2022; The All of US Research Program, NEJM 2019) will be used to conduct a retrospective cohort study to assess how proxies of socioeconomic status may affect the incidence and prevalence of sustained cardiac dysfunction from PPCM across different ethnicities in the US. The All of Us database focuses on enrolling people in the US from diverse groups that have historically been underrepresented in medical research. Therefore, it includes a more diverse population than the population targeted in the retrospective study conducted at the University of Pennsylvania in which only black women from Philadelphia, PA, were included. To further interrogate the impact that geographic location and population ethnicity may have on the prevalence of sustained cardiac dysfunction from PPCM, the results obtained from the “All of Us” database will be compared against data obtained from the UK Biobank. Expected Results: We expect that the socioeconomic proxies interrogated in this study will have a significant impact on the prevalence of sustained cardiac dysfunction from PPCM. Current knowledge is limited on how socioeconomic status affects sustained cardiac dysfunction resulting from PPCM. Previous studies have been done on populations restricted to small geographic areas and did not analyze factors such as food security, access to care, or disability status. Understanding how these factors affect the incidence and prevalence of sustained cardiac dysfunction from PPCM may be used to improve prevention, early diagnosis, and management of PPCM