Neurodegenerative Pathologies from Infectious Organisms and Responses to their Presence in Human Brains

Dear Colleagues,

The brain is unique from other body organs as it is located within the “blood–brain barrier” (BBB), a complex array of tightly conjoined and layered cells and connective tissue surrounding penetrant vascular, microvascular, vesicular, and lymphatic channels with wide-ranging and energy-demanding transport, homeostatic, and protective functions. Invasion into healthy brains by microbes (i.e., bacteria, fungi, protists, and archaea) and submicroscopic infectious agents (including viruses and prions) is limited by the BBB, but the brain requires highly effective immune defenses that, are only now being extensively detailed at molecular to systems levels. The brain is also exceptional in terms of the presence and number of very long-lived cells—neurons, certainly, but also other types, notably microglia. Long-lived does not equate to static, however; the dynamic restructuring of neurons occurs in developing and juvenile/pubescent, as well as mature adult, brain (e.g., dendritic trees and synapse presence and function), beyond which new neurons can be birthed and migrated into place in a few select regions.  Moreover, the critical involvement of multiple cell types in synaptic assemblages and in general neuronal function is now quite clear. 

Recent advances in various omics and microscopy-linked analytical technologies have enabled ever-more-detailed characterization of cells involved in immune defenses of the brain, revealing, for example, heretofore unknown multiplicities of microglial state and functional dynamics, as well as their relationship to chronic inflammation (which, persisting and progressing over years, can manifest as “inflammaging”).  In addition, the significance of biochemical crosstalk between brain/central nervous system immune function with peripheral systems, even extending to the microbe-rich and -diverse gut lumen, as well as penetration of nominally peripheral immune cells, such as macrophages, into locations formally within the BBB, are being increasingly appreciated, but with much remaining to be learned and understood. Even less-well-characterized at present are the roles of the extracellular matrix and trafficking therein.

In context of the above, the importance of infectious organisms and agents, although long ascertained in some instances and suspected in many more to be causes of various neurodegenerative conditions, and degradation of cognitive and motor function, is increasingly apparent. In addition, chronic inflammation, inclusive of brain microvasculature, compromises protective structures and function. Moreover, inter-pathogen interplays arise; for example, immune responses to bacterial incursions into brain tissue can provide opportunities exploitable by viruses to invade neurons and other cells.  Polymicrobial infection has been posited as a primary or contributing cause of late-onset/sporadic Alzheimer’s disease. Advances in technologies for detecting the presence and identities of infectious organisms and agents are now opening heretofore impossible avenues of investigation into their involvement in neurodegenerative processes. The complexities of microbial and submicrobial infectious agent biology and of the human brain and CNS, as well as the long timespans often involved (which we now can see may extend from prenatal events to old age), will require all that human science can muster, as well as continuing advances, in order to find ways of preventing or mitigating the all-too-often devastating human and economic tolls exacted by progressive or seemingly sudden-onset neurodegenerative maladies. At this juncture, the growing suspicion of COVID-19 coronavirus involvement in accelerated, delayed, or longer-term microvascular and neuronal degeneration will surely bring much of the above science to the foreground.

For this Special Issue of Life, we invite researchers from across the globe to share and/or review findings pertinent to infectious pathogen involvement in neurodegenerative conditions, with the brain/CNS as the main areas of emphasis.

Dr. Ronald A. Hill
Guest Editor

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• neurodegeneration
• brain
• inflammation (chronic)
• pathogens
• bacteria
• fungi
• viruses