Infections with Chlamydia pneumoniae and SARS-CoV-2 and Alzheimer's disease pathogenesis

Abstract

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the world, but our understanding of causation is still lacking. A current evidence-based hypothesis proposes that certain infectious agents initiate the neurodegeneration consistent with AD. Two infectious agents correlated to AD pathogenesis are Chlamydia pneumoniae (Cpn), a respiratory obligate intracellular bacterium, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus responsible for the COVID-19 pandemic. Both organisms may predispose susceptible populations to disease manifestations, such as AD.

Methods: This review focused on peer-reviewed original research and review articles evaluating the potential association of Cpn and SARS-CoV-2 with AD. Our focus included: genetic risk with expression of APOEε4 and other biomarkers common to AD including interleukin-6 (IL-6), chemokine ligand 2 (CCL2), neuropilin-1 (NRP1), and structural/functional aspects of the infectious processes and resultant neuroinflammation.

Results: Both Cpn and SARS-CoV-2 may infect the neuroepithelium of the olfactory system to enter the brain. Cpn binds to heparan sulfate proteoglycans for entry into mucosal cells. SARS-CoV-2 infects epithelia after binding to ACE2 receptors. Once inside the neuroepithelium, the pathogens may traffic to the olfactory bulbs. NRP1, an abundant receptor in AD, also potentiates SARS-CoV-2 infection. Furthermore, both pathogens may enter the systemic circulation for eventual entry through the blood brain barrier. The SARS-CoV-2 spike protein, in conjunction with CCL2, co-stimulates macrophages, resulting in IL-6 cytokine release. Likewise, Cpn infection leads to an increase of CCL2 and IL-6 cytokine release. The primary infection of either organism may lead to chronically elevated levels of IL-6 and secondary infection(s). Additionally, host APOEε4 expression appears to increase susceptibility to Cpn and SARS-CoV-2 infections.

Discussion: Cpn and SARS-CoV-2 may enter the brain through olfactory neuroepithelial cells and/or through the blood brain barrier. SARS-CoV-2 utilizes specific receptors for infection, while Cpn utilizes binding of proteoglycans. Neuroinflammation may be an outcome of infection with one or both organisms as observed by increased levels of CCL2 and IL-6 leading to AD pathogenesis. Genetic risk is noted for infection with both organisms with expression of APOEε4. Ongoing and future studies will further dissect mechanisms of infection with SARS-CoV-2 and Cpn as they may inform on causation and diagnostic factors for AD.

Keywords: Alzheimer’s disease; Chlamydia pneumoniae; SARS-CoV-2; blood-brain barrier; neuroinflammation; olfaction.

FIGURE 1

Search parameters flowchart. Chlamydia pneumoniae (Cpn) and the brain, COVID-19 and SARS-CoV-2 and the brain, and articles where the terms overlapped with Alzheimer’s disease were reviewed. Articles were identified for overlap with the olfactory system, ACE2, APOE status, NRP-1, IL-6, and lastly CCL2. Analysis of the articles revealed commonalities between the infectious processes and neuronal entry, neuroinflammation, co-infectivity and potential AD modulatory effects. Created in BioRender. Romanella (2025) https://BioRender.com/l7mlyv6.

FIGURE 2

The life cycle of Cpn. As Cpn is an intracellular bacterium, initial uptake of elementary bodies into the eukaryotic cell proceeds through an endocytic mechanism. Following cellular entry, transformation from elementary to reticulate bodies occurs within a phagosomal inclusion. Replication of reticulate bodies in the phagocytic inclusion occurs over 24–48 h followed by transformation back to elementary bodies and exocytosis from the cell occurs after 48–72 h. This exocytosis of elementary bodies allows infection of other cells in the nearby vicinity. Created in BioRender. Romanella (2025) https://BioRender.com/hrya3ng.

FIGURE 3

Infection of the olfactory system with SARS-CoV-2 and/or Cpn. The olfactory neuroepithelium is vulnerable to infections by respiratory pathogens. Receptors on these cells, such as NRP-1 and ACE2, can be utilized by SARS-CoV-2 for endocytosis. Other molecules such as Toll Like Receptor 4 (TLR4) and heparan sulfate proteoglycans may be used by Cpn for uptake. Direct infection via this pathway can bypass the blood brain barrier allowing access to other CNS structures. Created in BioRender. Romanella (2025) https://BioRender.com/hrvsh52.

FIGURE 4

SARS-CoV-2 entry by binding to ACE2 receptors. Following receptor binding to ACE2 receptors on the cell surface, SARS-Cov-2 is endocytosed and released into the cytoplasm for viral transcription and replication. APOEε4 chylomicrons may also bind ACE2 receptors. Following either endocytosis of SARS-CoV-2 and/or APOEε4 chylomicrons, the ACE2 receptors may be down regulated or degraded. Such receptor down regulation may lead to the pro-inflammatory buildup of Ang 1–7. Created in BioRender. Romanella (2025) https://BioRender.com/m244l3i.

FIGURE 5

Potential neuroinflammatory outcomes following infection. An indirect pathway to the CNS by the pathogens is via the Blood Brain Barrier. SARS-CoV-2 and Cpn in the bloodstream may result in damage to and/or infection of the blood brain barrier allowing the passage of pathogens into the CNS. The compromised blood brain barrier may further result in acute and long term chronic neuroinflammation with increases in pro-inflammatory cytokines IL-6 and CCL2. Such chronic neuroinflammation may initiate or exacerbate the pathologies observed in Alzheimer’s disease. Created in BioRender. Romanella (2025) https://BioRender.com/fi5988q.

FIGURE 6

Overlapping biomarkers: Cpn, SARS-CoV-2 Infections and Alzheimer’s disease. Overlapping relationships demonstrate how infection with these organisms may be a risk factor for the development of Alzheimer’s disease. Created in BioRender. Romanella (2025) https://BioRender.com/qwrsnij.