Genes and Infection

Carriers of the APOE4 variant, particularly those with two copies (homozygous), are at a much heightened risk for developing Alzheimer’s Disease.  The work demonstrating the role of APOE4 in the context of chronic infection deserves more attention.  While it remains to be duplicated and clarified, there is evidence suggesting that carriers of this gene are better “hosts” to various infections (HSV and even HIV).  Interestingly, APOE has also been identified in patients with other infection-associated diseases, like Asthma and Cardiovascular Disease.  We believe this is a valuable clue.

Research Studies

Apolipoprotein E4 enhances attachment of Chlamydophila (Chlamydia) pneumoniae elementary bodies to host cells

Microbial Pathogenesis, 2008.
Abstract- “Chlamydophila (Chlamydia) pneumoniae is an intracellular respiratory pathogen known to cause community-acquired pneumonia. Infection with this organism has been associated with atherosclerosis, inflammatory arthritis, and other chronic diseases, many of which also have been associated with possession of the epsilon4 allele at the APOE locus on (human) chromosome 19. An earlier study from this laboratory suggested that some relationship exists between apolipoprotein E4 (apoE4), the product of the epsilon4 allele, and the pathobiology of C. pneumoniae. A standard attachment assay and real time PCR targeting a sequence on the C. pneumoniae chromosome were used to monitor host cell binding of elementary bodies (EB) of that organism. Our data indicate that 3-fold more EB of strain AR-39 attach to an epsilon3 homozygous human cell line transfected with a plasmid expressing the epsilon4 coding sequence than to the same cell line harboring empty vector, vector containing an irrelevant insert sequence, or vector containing the DNA sequence encoding apoE3. The quantitative real time data were confirmed by immunolabeling of chlamydial inclusions in parallel attachment and infection assays. Experiments using Chlamydophila trachomatis EB showed no enhancement of attachment in the presence of the epsilon4 allele in any assays. These observations indicate that apoE4 enhances attachment of C. pneumoniae EB, but not those of C. trachomatis, to target host cells.”

The load of Chlamydia pneumoniae in the Alzheimer’s brain varies with APOE genotype
Microbial Pathogenesis, 2005.
Studies from this laboratory have indicated that the intracellular eubacterial respiratory pathogen Chlamydophila (Chlamydia) pneumoniae is commonly found in brain regions displaying characteristic neuropathology in patients with late-onset Alzheimer’s disease (AD) but not in congruent samples from non-AD control individuals. In later work, we provided evidence suggesting that some relationship exists between the APOE epsilon4 gene product and the pathobiology of this organism.
Methods- In the present report, in situ hybridization analyses indicated that the number of C. pneumoniae-infected cells in affected brain regions of epsilon4-bearing AD patients was higher overall than that in congruent brain regions from AD patients lacking that allele.
Results- Quantitative real-time PCR analyses of AD brain tissue samples demonstrated that actual bacterial burden in those samples varied over several orders of magnitude, but that samples from epsilon4-bearing patients did have significantly higher bacterial loads than did congruent samples from patients without the allele (ANOVA, p<0.05).
Conclusion- These results may explain in part the observations that epsilon4-bearing individuals have a higher risk of developing AD, and that such patients progress more rapidly to cognitive dysfunction than do individuals lacking this allele.

PSEN1DE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human iPSC-Derived Microglia

Stem Cell Reports, 2019.
Abstract- “Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.”

Apolipoprotein E–Deficient Mice Develop an Anti–Chlamydophila pneumoniae T Helper 2 Response and Resist Vascular Infection
Journal of Infectious Disease, 2010.

“Background- Hypercholesterolemia could inhibit the immune response against various pathogens. No information is available about its impact on the immune response toward Chlamydophila pneumoniae.
Methods- Apolipoprotein E (apoE)-deficient and wild-type mice fed a normal diet were infected with a single intranasal inoculation of viable C. pneumoniae.
Results- Whereas interferon gamma concentrations (T helper 1 response) were similar in the lungs and spleen of apoE-deficient and wild-type mice, increased concentrations of interleukin 10, interleukin 6, and interleukin 4 (T helper 2 response) were found in the lungs of apoE-deficient mice. The spleen B lymphocyte percentage and interleukin 4 levels and serum specific antibody titers were higher in apoE-deficient mice. C. pneumoniae infection was facilitated neither in the lungs nor in the aorta of these mice. On the contrary, the number of apoE-deficient mice with detectable levels of bacterial DNA in the aorta was clearly decreased. When low-density lipoprotein receptor-deficient mice fed a normal diet were similarly infected, no difference in the interleukin 4 concentration and infection level was observed in the lungs and no protection was found in the aorta.
Conclusions- Mild hypercholesterolemia in mice does not facilitate C. pneumoniae persistence in the vascular wall. ApoE deficiency, rather than mild hypercholesterolemia, probably favors the development of an unusual anti-C. pneumoniae T helper 2 response and protects against vascular infection.”