The blood-brain barrier and pathogens

Keywords: :

• Cryptococcus neoformans
• Listeria monocytogenes
• Plasmodium falciparum
• HIV
• HTLV-1
• blood-brain barrier
• endothelial cells

Infections of the central nervous system (CNS) are major causes of morbidity and mortality in both the developing and developed world.^1-3 The variety of pathogens that could infect the brain is only paralleled by the complexity of the various pathways involved in the pathogenesis of such infections. Bacterial pathogens such as Listeria monocytogenes, fungal pathogens such as Cryptococcus neoformans, parasitic pathogens such as Plasmodium falciparum, Toxoplasma gondii and Trypanosoma crusii and viral pathogens such as HIV and HTLV1 are only examples of the types of pathogens that could infect the CNS.

Regardless of the type of infection, organisms trying to enter the CNS have to cross the blood-brain barrier (BBB), a formidable “wall” that protects the brain and the spinal cord. This barrier is composed of the neurovascular unit that includes vascular endothelial cells, partially surrounded by pericytes, astrocytes and some neurons.⁴ Multiple depictions of the BBB are included in this issue of Virulence in the reviews by Liu et al.,⁵ Masocha et al.,⁶ Miller et al.⁷ and Feustel et al.⁸ It is reasonable to think of the BBB as an impenetrable “Hadrian’s Wall,” the famous structure that constituted the most heavily fortified border of the Roman Empire.⁹ In principle, the BBB should help protect the CNS from circulating pathogens and from the free movement of soluble proteins and circulating immune cells thereby preserving the CNS function. In this timely issue of Virulence the reader will see that this concept of impenetrable BBB is merely wishful thinking. Indeed, pathogens have devised several mechanisms by which they can traverse the BBB and infect the brain. An overview of these mechanisms makes a student of history think mostly of ancient tactics of war.

Indeed, Rénia and colleagues¹⁰ on page 193 of this issue discuss how malaria parasites enter the brain by multiple mechanisms including damaging the BBB by loosening the tight junctions between endothelial cells or focal rupturing the BBB causing brain hemorrhage. This is reminiscent of the ancient war technique of “ramming” the wall that protects the brain.

Another example of forceful entry into the brain is one mechanism by which the pathogenic yeast Cryptococcus neoformans can cross the BBB. In their review on page 173, Liu et al.⁵ discuss a recent paper by Shi and colleagues¹¹ where the authors used intravital microscopy to show that cryptococcal cells become mechanically trapped in small brain capillaries and then force their way and transmigrate across the endothelium to the brain parenchyma.

Liu et al.⁵ discuss also how C. neoformans uses another ancient war tactic to cross the BBB. Just as Odysseus and his ancient Greek co-warriors used a wooden horse to get through Troy’s Dardanian gates and destroy the city,¹² C. neoformans infects monocytes and then uses these cells to carry it through the BBB and infect the brain. The pathogen cells are then released from the monocytes after penetration.

Another organism that uses the Trojan horse tactic to cross the BBB is Toxoplasma gondii. As discussed in their papers, Masocha and Kristensson⁶ and Feustel et al.⁸ review how Toxoplasma can infect monocytes and dendritic cells and uses these cells to cross the BBB.

Pathogens can also use treachery, another tactic of ancient and modern war, to enter the brain. As discussed in the review by Miller and colleagues,⁷ HIV can infect the host’s own endothelial cells, the first line of defense against CNS invasion and either induce their apoptosis or alter the integrity of the BBB. Of course HIV can also use other mechanisms such as altering the BBB by inducing cytokines or via the direct effects of the viral proteins Tat or gp120.

Another mode of treachery is used by Listeria monocytogenes to enter the brain. Listeria can use the host’s peripheral nervous system itself in a retrograde infection model to enter the CNS. Not surprisingly, Listeria can also use the Trojan horse model or can enter the brain directly by infecting endothelial cells.¹³

While we have learned a lot in the past decade about how pathogenic organisms invade the CNS, much remains to be learned. Developing in vitro models of CNS infections will be crucial for advancing the field. In this context, Siddiqui and colleagues¹⁴ present a novel model of the BBB that would be useful for studying parasitic and other infections of the CNS. Such a model would also be useful for testing new drugs that could perhaps delay or slow penetration of the BBB by pathogenic organisms.

Future areas of investigation that would help propel the field include development of new animal models for CNS infections. While non-mouse rodent models are helpful, development of mouse models is crucial. With increased availability of mice with targeted deletion of virtually all mouse genes, developing mouse models of CNS infections may allow detailed dissection of pathways involved in CNS invasions by various organisms.

Another area of future investigation would be the use of new technologies to analyze the transcriptomes of various components of the neurovascular unit before, during and possibly after infection. Such technologies include RNAseq,¹⁵ which allows quantitative analysis of the transcriptomes of cells using small amounts of starting material. Coupled with new approaches for proteomic analysis,¹⁶ these new methodologies are likely to significantly advance our understanding of the pathogenesis of CNS infections. This would also improve our ability to identify new targets for treatment of such infections.

In addition to understanding the host determinants of CNS invasion, understanding virulence elements that can promote the ability of pathogenic organisms to traverse the BBB is of almost equal importance. Identifying virulence factors that promote binding of organisms to brain endothelial cells, or survival of organisms in monocytes would significantly enhance our ability to identify novel targets to prevent, slow down or treat CNS infections.

It is an exciting time for those involved in research to understand the pathogenesis of CNS infections. The increased knowledge of the structure and functions of the BBB and the new technologies available for research promise to usher a new era of advancement in the field.