How CNS-Invasive Parasites Evade the Brain’s Immune System

 

Part 1 – Rehan Syed

 

Introduction

Parasites can be defined as organisms that engage in a symbiotic relationship with another organism while causing some form of harm to its host.[1] The human body has evolved to protect itself from such threats, and is well-equipped with specialized cells and other mechanisms with which it can prevent or fight off infiltration by foreign organisms. Thus, for a parasite to survive, proliferate and otherwise be successful, it must find ways around these defenses.  Different parasites employ various mechanisms to evade their hosts’ immunological systems in order to survive in the niche environments to which they are adapted.

 

Some of the most extraordinary parasites are those that manage to infiltrate and infect the human central nervous system (CNS), and especially the brain. The brain is an exceptionally crucial organ within the human body, and because of its importance it is also one of the most well-defended environments within the body. In fact, the brain is so well-guarded that it comes equipped with its own immune system that differs significantly from the rest of the body’s, and even the body’s own immune cells foreign to the brain often cannot access this sensitive area. To access and thrive in the brain is an advantageous prospect for a parasite due to a variety of factors, such as easy access to nutrition and the ability to avoid much of the body’s normal immune response.[2] However, to live in the brain, a parasite must first reach it and then be able to evade the immune response unique to the CNS. In order to understand how parasites might evade this specialized immune system, it is first necessary to understand the basics of brain immunology.

 

Brain Immunology

The blood-brain barrier. (Francis, Karen, Johan van Beek, Cecile Canova, Jim W. Neal, and Philippe Gasque)

 

The brain’s first, and perhaps its most important, line of defense is called the blood-brain barrier (BBB). The blood-brain barrier’s primary function is to prevent hydrophilic micromolecules and macromolecules in the blood from entering the extracellular space of the CNS. Endothelial cells that form the capillaries and venules in the CNS are connected by impermeable tight junctions which prevent all but a select few hydrophobic molecules and hormones from penetrating into the brain from the blood-brain interface.[3] Thus, it is impossible for large organisms such as most parasites circulating in the blood to enter the brain via these tight junctions. Some portions of the brain such as the choroid plexus and preoptic recess lack the blood-brain barrier, but usually employ other barriers similar to the BBB such as the blood-cerebrospinal fluid barrier or the blood-retinal barrier.[4] If pathogens somehow manage to penetrate the BBB, they must then contend primarily with what are known as microglia.[5] Because a  “normal” immunological response as it occurs in the rest of the body would be too damaging to the sensitive densely packed neurons that make up the brain, the combined function of antibodies, macrophages, T-cells and other immune response components must all be performed by microglia.[6] To suit their form to their function, microglia are extremely plastic and can develop a variety of structures to perform the specific role required of them.[7] Between their various types microglia can detect the presence of a foreign antigen, phagocytose the foreign body or parasite, present the foreign antigen, release cytokines, activate other microglia, recruit a number of leukocytes such as antigen-presenting T-cells to selectively cross the blood-brain barrier, and recruit other cells such as astrocytes and neurons to aid in the repair of damaged tissues. Thus, the brain is far from a “safe zone” for an invading parasite.

 

CNS-Invasive Parasites

In spite of this, a large number of parasites do manage to successfully infiltrate and infect the CNS. A definitive list is difficult due to the sheer number of parasites which can accomplish CNS infection given favorable conditions, but such species include: Acanthamoeba astronyxis, A. castellanii, A. culbertsoni, A. hatchetti, A. keratitis, A. lugdunensis, A. palestinensis, A. polyphaga, A. quina, A. rhysodes, Angiostrongylus cantonensis, Balamuthia mandrillaris, Baylisascaris procyonis, Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Entamoeba histolytica, Gnathostoma spinigerum, Histoplasma capsulatum, Lagochilarscaris minor, Naegleria fowleri, Paracoccidiodes brasiliensis, Paragonimus westermani, P. mexicanus, Plasmodium falciparum, P. vivax, P. ovale, Psuedellescheria boydii, Schistosoma mansoni, S. haematobium, S. japonicum, Sporothrix schenckii, Strongyloides stercoralis, Taenia solium, T. multiceps, T. serialis, Toxocara canis, T. cati, Toxoplasma gondii, Trichinella spiralis, Trypanosoma brucei gambiense, T.b. rhodesiense, Trypanosoma cruzi, and Xylophypha bantiana, among others.

 

Natural vs. Opportunistic CNS Parasites

Parasites that infect the CNS can be separated into two broad categories: natural CNS parasites, and opportunistic CNS parasites. Natural CNS parasites can infiltrate and infect the CNS of a healthy individual, and although the mechanisms by which they do this differ by species, this usually involves the targeted attacking of the blood-brain barrier’s endothelial cells to access CNS tissue. On the other hand, opportunistic CNS parasites do not characteristically infect the CNS except in immunocompromised patients; this is usually due to the body’s inability to effectively resolve inflammation of the BBB’s endothelial cells, which increases the permeability of the barrier and allows larger molecules and parasites to enter the CNS capillaries from the bloodstream. Considering species numbers alone, there are far fewer natural CNS parasites than opportunistic ones. However, it should be noted that natural CNS parasites are also much more likely to be successful at infecting their host if the host is immunosuppressed.

 

Due to the sheer number of parasite species and the variety of mechanisms by which they evade the immune system to successfully infect the brain, only five prominent parasites will be explored in greater depth below. These parasites are the amoeba Naegleria fowleri (a natural CNS parasite), the protozoa Toxoplasma gondii (an opportunistic CNS parasite), the tapeworm Taenia solium (a natural CNS parasite), the protozoa Plasmodium falciparum (a natural CNS parasite), and the protozoa Trypanosoma brucei (a natural CNS parasite).

 

Naegleria fowleri[8]

 

Naegleria fowleri is one of the few known free-living amoebae that infect humans. The amoeba is a natural CNS parasite, and causes a condition known as primary amebic meningoecephalitis (PAM) that has a case fatality ratio of 97%. However, many N. fowleri are non-pathogenic. N. fowleri thrives in a warm, moist environment and can be found in soil or bodies of water.

Naegleria fowleri amoeba. (Division of Parasitic Diseases, CDC)

 

Infiltration of the Brain

It is unclear why pathogenic N. fowleri targets the brain, but access to the CNS is tied intimately to the way the amoeba enters the host. Swimming in fresh water by children or adults exposes them to the suspended amoebae, which enter the nasal cavity of the potential host. While rare, some N. fowleri will proceed to penetrate the roof of the nasal cavity. From this point, they proceed to attach themselves to the nasal mucosa, migrate down the olfactory nerves and cross the olfactory epithelium, cross the cribriform plate, and penetrate brain tissue. N. fowleri uses the brain vasculature to reach the meninges surrounding the frontal lobes, in which they multiply and destroy CNS tissue. Adhesion plays a crucial role in the amoeba’s ability to quickly access its infection target. This is due in part to the amoeba’s possession of a surface protein that is similar to the human integrin-like receptor that provides exceptional bonding to fibronectin, one of many extracellular matrix glycoproteins that make up the structure of the matrix of the host’s cells. Efficient locomotion and a relatively direct access to the site of infection minimize opportunities for a strong immune response to be launched by the host prior to the parasite reaching the sensitive brain tissue.

 

Coping with the Immune System

While the details of how CNS-infective amoebae cope with the human host’s immune response are not yet fully understood, N. fowleri does seem to possess mechanisms with which it evades the host immune response. The amoeba attacks cells by tragocytosis and the release of a plethora of cytolitic enzymes, including aminopeptidases, hydrolases, esterases, acid and alkaline phosphatases and dehydrogenases. These enzymes produce a highly cytopathic effect on the host’s cells, and this likely not only contributes to the N. fowleri’s virulence but also its ability to successfully infiltrate the host by damaging impeding cells.

 

However, even more importantly N. fowleri is highly resistant to lysis by the host’s cytolytic molecules such as cytokines TNF-α, IL-1 and MAC C5b-C9. Research suggests eukarytoic cells such as mammalian erythrocytes, neutrophils and tumor cells utilize complement-regulatory proteins to protect themselves from lysis by the complement system of the innate immune system. N. fowleri seems to have adapted to also carry these complement-regulatory proteins, giving it resistance to complement lysis. Complement lysis is further prevented by the N. fowleri’s shedding of the membrane attack complexes (MAC) that designate the parasite for lysis.[9]

 

Furthermore, it has yet to be shown that the human body’s acquired immune response has any effect on N. fowleri. While it is the case that antibodies to the amoeba are found in patients exposed to N. fowleri, they are usually low in number and do not increase noticeably in pathogenic cases. As such, it is the host’s innate immune response that is most capable of eliminating N. fowleri, and to which N. fowleri has adapted its primary evasive techniques.

 

Vulnerabilities to the Host’s Immune Response

Yet, N. fowleri is in fact vulnerable to parts of the host’s innate immune defense. Although TNF-α does not directly affect the amoeba, it does promote neutrophils to attack the parasite. Activated macrophages present prior to the parasite’s infiltration of the brain and microglia within the brain itself also seem to play a large role in combating the parasite. However, the immune response cascade triggered by these immune cells can contribute to a buildup of cytokines and other cytolitic molecules the N. fowleri is resistant to, causing lysis of nearby neuronal cells, a further collection of organic debris and further immune response, hyperinflammation and a breakdown of the blood-brain barrier, and in doing so aid the pathogenicity of the amoeba more than help control it.

 

The disease course of an N. fowleri infection is usually short for this reason, but it is still unclear whether N. fowleri can survive this eventual avalanche of immunological response and replicate faster than it is destroyed. Studies in animal models suggest that chronic N. fowleri infection may be possible as the N. fowleri can reproduce faster than the pressures acting against it can control it, but whether this holds true for human hosts has yet to be shown.

 

Toxoplasma gondii[10]

 

Toxoplasma gondii is a common parasitic protozoan that can be found in a variety of environments and with a high prevalence within a given population. Seropositivity rates among pregnant women are as high as 80-90% in Paris and regions of Africa, and exceptionally low in countries such as Japan and Australia. Most infections by T. gondii are asymptomatic, but the risk of a CNS infection increased drastically in immunocompromised patients, young children, and cases of congenital transmissions. Pathogenic infection by this opportunistic CNS parasite can cause encephalitis and other neurological diseases, among other deleterious effects in other parts of the host. One of the more common causes of pathogenic infection is the reactivation of a latent infection as a result of the immunosuppressant effect of AIDS in comorbid patients.

Toxoplasma gondii

 invading a host cell. (Boothroyd, John C. and Jean-Francois Dubremetz)

 

Invasion of the Host and Development of Cysts

T. gondii has a unique technique of hiding in its host’s cells. Upon penetrating the tissue of the intestines, the protozoa infect a variety of the host’s cells including macrophages. Among other mechanisms, the T. gondii partially inhibits the production of nitric oxide by the macrophage host cell, preventing the process of oxidative burst that would normally kill the parasite.[11] On the whole this is an effective technique for the protozoa. However, T. gondii is not able to prevent this oxidative burst in infected monocytes, which can clear the protozoa intracellularly. Furthermore, lymphokines such as gamma interferon can activate macrophages and other cells to destroy T. gondii. Yet another danger T. gondii faces is that the process of penetrating the host’s cells and replicating can trigger an inflammatory response that can damage nearby intestinal epithelium; this exposes the tissue to foreign bodies such as gram-negative bacteria that can stimulate a full-blown immune response. To compensate for this, T. gondii must actively down-regulate the immune response to prevent itself from being eliminated in the potential immunological action. Gram-negative bacteria are of exceptional danger due to the abundant presence of lipopolysaccharide (LPS) that can trigger a host immune response, but T. gondii posses genes that code to suppresses the LPS-induced signaling pathway that leads to the production of IL-12, TNF-a and other cytokines.[12]

 

This provides the opportunity for T. gondii to thrive and proliferate. The protozoa spread across the body, and can infiltrate the brain. The exact process by which T. gondii is able to cross the blood-brain barrier is not currently well understood, but the protozoa seem to access the brain primarily by two methods. One method is by transport within a white blood cell that is able to move across the blood-brain barrier; while this is possible to some degree, the large sizes of macrophages and the ability of monocytes to eliminate T. gondii make this a difficult process.[13] Another method used by T. gondii is active infiltration of the blood-brain barrier’s endotheilial cells.[14] This active migration across the barrier likely contributes much more to T. gondii’s presence in the brain compared to the “Trojan horse” technique.

 

Still, indefinite immunosuppression eventually lowers the survivability of the host, and consequently the parasite’s likelihood of survival as well. The T. gondii tachyzoites in the human tissue are also simultaneously slowly pressured by both the host’s innate and acquired immune responses. To evade elimination, tachyzoites form pseudocysts and subsequently cysts, which are immunologically inert. These cysts remain dormant in the tissue until they can become reactivated. The host’s innate immune system acts against these cysts to prevent their reactivation in normal, healthy conditions, although it’s unclear by which mechanism this is managed. Evidence suggests cysts periodically attempt to rupture and reform new cysts, but are limited by pressures from the host’s immune system.

 

Reactivation in Immunosuppressed Individuals

However, the immune systems of immunosuppressed patients may fail to keep these cysts from reactiving, allowing a full-blown reinfection to occur. The lack of antibodies in the brain due to the blood-brain barrier makes it more likely for cysts in the CNS to have persisted and not be cleared as the protozoa in other tissues might have been. As a result, a strong reinfection in an immunocompromised state is often centralized in the CNS and can lead to the severe pathogenesis associated with toxoplasmosis. Toxoplasmosis in the brain often consists of necrotizing encephalitis and associated inflammation, to which microglia respond by forming nodules in attempts to contain the infection. Oftentimes this containment effort is simply ineffective due to the immunocompromised nature of the host. At this stage, the T. gondii can simply reproduce and infect faster than the microglia can control them, and the immune response is defeated. The clinical effects of this uncontrolled infection are often dire.

 


Part 2 – Adnan Syed

 

Human African Trypanosomiasis

 

Two distinct forms of trypanosomiasis exist: Trypanosoma cruzi is responsible for American trypanosomiasis (or Chagas disease), while Trypanosoma brucei subspecies gambiense and rhodesiense cause African trypanosomiasis. CNS infection by Trypanosoma cruzi is rare, though more cases have been observed recently due to rising co-infections of HIV in Latin America[15]. On the other hand, CNS infection by Trypanosoma brucei subspecies is far more common, with symptoms that have led many to refer to African trypanosomiasis as “sleeping sickness.” For the purposes of this paper, “trypanosomiasis” will refer to the African form unless otherwise indicated.

Human African trypanosomiasis in infected blood smear.

(Proceedings of the National Academy of Sciences)

 

Survival Prior to CNS Infection

It is very difficult for parasites to become established in the CNS, and so trypanosomiasis hemoflagellates have developed a variety of techniques to invade and persist in the face of the human body’s robust immune response.

 

Upon entry into the bloodstream or mucous membranes by the bite of the Tsetse fly vector, the trypanosomes immediately begin to replicate and invade local tissue. Still non-cerebral, trypanosomes survive the host’s adaptive immune response by cycling expression of a variant surface glycoprotein (VSG), expressing only one at any given time[16]. Host antibodies initially cannot penetrate the shielding created by the VSG, but soon an IgM response specific to the VSG being expressed is launched that successfully destroys most of the trypanosomes in the blood. However, some survive by shedding this coat and subsequently expressing a different VSG than that targeted by the IgM response, and therefore are able to proliferate quickly and cause another wave of parasitemia. Because over 1,000 antigenically distinct VSG genes exist within the trypanosomes, waves of parasitemia can persist for long durations. Trypanosomes also express a surface protein similar to one found in Leishmania, which may protect it from being lysed by complement proteins[17]. Furthermore, infection suppresses normal B cell and T cell immune response, as well as secondary antibody responses other than that of IgM. Trypanosomes are thought to suppress the immune response by triggering prostaglandin E2 and E12 release, lowering cytokine production and perhaps altering sleep patterns (a characteristic symptom of sleeping-sickness). This immunosuppression is why secondary opportunistic infections often occur in patients with trypanosomiasis. While many trypanosomes continue these cycles in the blood, some may successfully infiltrate the CNS.

Waves of parasitemia following VSG cycling in African trypanosomiasis infection.

(Ashall, Frank)

 

Infiltration of the CNS

The mechanism of CNS invasion is not fully understood, but it is hypothesized that trypanosomes penetrate through either the blood-brain barrier or the blood-cerebrospinal fluid barrier[18]. When trypanosomes cause local inflammation at such a barrier, a variety of cytokines, eicosanoids, and neutrophils arrive to mediate the inflammation. Mononuclear cells soon migrate to the site, as well as serum proteins to be transferred to the cerebrospinal fluid. The arrival of this immune response increases permeability of the barrier by a variety of mechanisms. Endothelial cells become more permeable when exposed to cytokines TNF-a, IL-1 and IL-6. Intercellular adhesion molecules ICAM-1 and ICAM-2 within barrier cells that normally assist leukocyte migration also are up-regulated by exposure to IFN-g and IL-1. Furthermore, many of these cytokines induce the expression of inducible nitric oxide synthase, with nitric oxide further enhancing local permeability. Nitric oxide also activates synthesis of the aforementioned prostaglandins E2 and E12[19].

 

The precise route of penetration is unknown, but independent studies suggest four possibilities[20]. Preferential localization around brain parenchyma protected by the blood-cerebrospinal fluid barrier rather than the blood-brain barrier suggests it may be easier to penetrate the former than the latter. It is possible that trypanosomes enter through the choroids plexus epithelium and into the cerebrospinal fluid, in which it can travel to and infect brain parenchyma. Alternatively, it may pass through brain capillaries and then into cerebrospinal fluid and brain parenchyma. It once was thought that destruction of tight junctions at the blood-brain barrier was necessary for CNS infection, but recent evidence suggests that infection can occur without altering tight junctions. It therefore is believed that trypanosomes may travel alongside or even inside leukocytes, through the aforementioned up-regulation of intercellular adhesion molecules. Once inside the CNS, trypanosomes take advantage of the limited local immune response for their own proliferation and protection.

Comparison of general capillary with brain capillary and additional structures constituting the blood-brain barrier.

(Enanga, et al.)

 

Regulation of the Immune Response After Infection

Late-stage sleeping sickness can have many associated neuropathologies, including “perivascular cuffing… nonspecific lymphoplasmacytic meningoencephalitis… microglial hyperplasia, reactive astrocytes, and infrequent demyelination”[21]. Despite the immunosuppression often found in those infected, hosts often continue to mount an immune response, with MHC class I and MHC class II, B and T cells, and macrophages all being found in inflamed tissue. Animal model studies suggest that many of the symptoms of trypanosomiasis are caused by this pathology and immune response in specific areas of the brain, particularly regions where the blood-brain barrier is relatively weak.

 

Aspects of the immune response actually benefit and may be crucial to the survival of the trypanosomes. The increased production of nitric oxide (stimulated by cytokines such as IFN-g) may induce the apoptosis of threatening inflammatory cells and lengthen parasite survival[22]. Increasing prostaglandin levels and activating astrocytes that can inhibit T-cell proliferation bestows the parasites a substantial level of protection. While certain aspects of the immune response are suppressed, the simultaneous increase in CD8+ T cells and the resulting increased expression of IFN-g and MHC class I molecules is thought to act as a growth factor that enhances the parasites’ ability to survive. As such, trypanosomes may infect the CNS as a means to readily access this growth factor while using the brain as an immune-privileged site to avoid the full immune response. In doing so, the trypanosomes are able to persist and even flourish within the CNS until the associated cerebral damage overcomes the host.

 

Cerebral Malaria

 

Cerebral malaria is an encephalopathy associated with infection by Plasmodium falciparum, and is most often characterized by unarousable coma and high risk of death if left untreated[23]. Only P. falciparum is currently thought to cause cerebral malarial; though rare cases of unarousable coma have been associated with infections of P. malariae and P. vivax, it is suspected that co-infection by P. falciparum was present.

 

Survival in the Liver and Blood

Once a host is inoculated by the bite of a mosquito vector, the injected sporozoites enter the exo-erythrocytic cycle and then the erythrocytic cycle. To avoid the resulting immune response, the parasites use variant surface glycoproteins to shield themselves from host antibodies. Upon each reproductive cycle a new VSG is expressed, preventing the specific response from properly targeting and eliminating the parasites. An important feature of P. falciparum is its cytoadherence characteristic, resulting in the sequestration of mostly parasitized erythrocytes in tissues, particularly in small blood vessels throughout the body[24]. This packing of erythrocytes does not necessarily alter total blood flow, but is associated with local hypoxia. In some vessels this can result in engorgement, hemorrhaging, deformation, and occlusion. The mechanical sequestration of erythrocytes in cerebral capillaries was once thought to be the primary cause of cerebral malaria, but more recent studies have suggested an alternative mechanism involving the host inflammatory response.

Obstructed microvasculature by erythrocytes infected by P. falciparum.

(Brown University)

 

Alteration of the Inflammatory Response

Tumor necrosis factor (TNF) is now thought to play a central role in the mechanism of cerebral malaria due to its association with malarial fever and cerebral malaria[25]. It is now believed that schizonts bind to endothelial cells and subsequently rupture. This rupturing and the accompanying release of toxins are thought to be responsible for malarial paroxysm. However, the released toxins also up-regulate TNF production in leukocytes, which stimulates increased expression of intercellular adhesion molecule-1 (ICAM-1) and possibly the cytoadherence receptor E-selectin. Additional parasitized cells can subsequently adhere to endothelium more readily, obstructing small vessels and causing pathology through a purely mechanical mechanism. However, it is now thought that the cytokines produced during a malarial infection (particularly IFN-g and TNF) and possibly toxins released during schizont rupture stimulate macrophages to release high amounts of nitric oxide. Nitric oxide could subsequently pass through the blood-brain barrier and act as a powerful inhibitor of neurotransmitter activity, anesthetizing the patient to the point of unarousable coma. This mechanism is still not fully understood, but may explain why recovery from such comas is so swift and complete.

Schizont stimulation of TNF production and subsequent ICAM-1 and nitric oxide expression.

(Peterson, Phillip K., and Jack S. Remington, eds.)

 

Taenia solium Neurocysticercosis

 

Taenia solium, also known as the pork tapeworm, can cause disease in humans when ingested[26]. Ingestion of infective larvae or cysticerci in undercooked or cured pork results in the development of adult worms within the new host’s intestines. However, ingestion of viable eggs instead involves the disintegration of the egg’s outer shell in the intestines, allowing the embryo or oncosphere to penetrate the intestinal wall and enter the bloodstream. Once in circulation, these may settle in many types of tissue. Sometimes they are able to pass through the blood-brain barrier and enter the CNS. The mechanism for bypassing the blood-brain barrier is not fully understood, and while some suspect enzymes may weaken this barrier, others believe special permeability allows passage without damaging the barrier[27]. Once inside the CNS, the parasites settle and begin to develop into cysts.

Brain parenchymal cysticercosis.

(Biocrawler)

 

Neurocysticercosis

The development and persistence of living fluid-cysts (metacestodes) within the CNS is known as active neurocystercosis, and is the most common parasitic CNS infection worldwide[28]. Symptoms of neurocysticercosis are largely caused by the direct growth of these cysts on cerebral parenchyma or growth in and blockage of cerebrospinal fluid-filled cavities. Once formed into cysts within the CNS, the metacestodes are significantly more shielded from the immune response than when in their egg or larval stages. Living within the immune-privileged CNS grants the cysts some protection, but they must still confront the host’s immune response as it strengthens. However, the cysts have developed several sophisticated mechanisms to evade and even exploit this immune response.

 

T. solium metacestodes are closely associated with suppression of the host’s immune response, particularly of CD4+ T cells in the peripheral blood through apoptosis[29]. Cysts may be able to protect themselves from the innate immune system by directly inhibiting neutrophil and eosinophil function, as the white blood cells have been seen enveloping metacestodes with no signs of harm[30]. It is suspected that this may be achieved by preventing the attacking cells from producing key proteins or by blocking their ability to target the cysts. Other studies have shown increased host immunoglobulin levels around living cysts compared to dead ones, suggesting that living cysts use these to disguise themselves as host cells from the humoral immune response[31]. It is even thought that T. solium cysts may stimulate T-cells to form immunoglobulins that can then be digested as a primary protein source. As such, these metacestodes are both protected from much of the immune response and can selectively elevate aspects of the response for their own benefit.

 

Challenges to Treatment of Parasitic Infections of the CNS

 

Considerable research has been conducted to achieve a substantial understanding of the major mechanisms of pathology for several parasitic infections of the CNS. Though many uncertainties remain, recent discoveries regarding evasion and even exploitation of the host’s immune response have enabled the development of efficacious medical interventions. However, many of these interventions have significant shortcomings that need to be addressed with future research. For instance, while the treatment of viable T. solium cysts has been shown to be highly effective, treatment of calcified lesions (dead cysts) or use of corticosteroids is poorly studied[32]. In the case of human African trypanosomiasis, there is considerable controversy regarding the treatment of post-treatment reactive encephalopathy. A better understanding of the mechanisms associated with specific parasitic infections will inform safer and more efficacious treatment options for these serious diseases.

Comparison of transvascular and transcranial neurotherapeutic delivery.

(Pardridge, William M.)

 

Another concern is the delivery of neurotherapeutics to the CNS, as many compounds cannot penetrate the blood-brain barrier (BBB) or blood-cerebrospinal fluid barrier. In addressing this, it is important to determine whether the targeted parasite can persist or proliferate in the relatively nutrient-limited cerebrospinal fluid. This will determine what barriers the drug being developed must pass. Many techniques have been developed to deliver drugs to the CNS, but many are not feasible for safe and widespread treatment (such as cerebral injection or hyperosmolar BBB disruption)[33]. Transvascular delivery through the BBB remains the most desirable method of delivery. Breakthroughs in nanotechnology have made nanoparticulate delivery systems an attractive method, especially if delivered through nasal routes. However, whether such interventions can be made sufficiently efficacious yet low-cost for administration to highly burdened populations in developing countries remains to be seen.

 

Conclusions

           

Though only a relatively limited number of parasites can penetrate and infect the CNS, an enormous variety of immune evasion, suppression, and exploitation techniques can be seen employed by these parasites. Though strategies may differ greatly, they are united by several common themes. Infections of the CNS are often characterized by a limited immune response due to the danger of inflammatory damage. However, it is apparent that even within the CNS parasites must cope with host defenses or else perish. Penetrating the blood-brain barrier or blood-cerebrospinal fluid barrier is a serious challenge for all parasites, and only some can successfully invade the CNS. In those that can, evasion or suppression of the immune response is nearly universal, though the means by which this is achieved certainly is not. Several parasites not only endure this immune response, but selectively amplify elements of it for their own benefit. In this way, these parasites have managed to flourish – though often at the expense of their host. Detailed studies have provided insight into the mechanisms employed by these parasites and have informed valuable medical interventions. However, there is a real need for further investigations to refine or develop new treatments that are not only highly efficacious but also readily accessible. Understanding each parasite’s interactions with its host’s immune response is an important step in the development of such interventions and the eventual treatment of these parasitic infections.


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[1] Merriam Webster Online.

[2] Manzo, Andrea.

[3] Janzer, Robert C., and Martin C. Raff.

[4] Laterra, John, Richard Keep, Lorris A. Betz, and Gary W. Goldstein.

[5] Trivedi, Bijal.

[6] Kreutzberg, G. W.

[7] Gehrmann, Jochen, Yoh Matsumoto, and Georg W. Kreutzberg.

[8] Scheld, W. Michael, Richard J. Whitley, and David T. Durack, eds.

[9] Marciano-Cabral, Francine and Guy A. Cabral.

[10] Scheld, W. Michael, Richard J. Whitley, and David T. Durack, eds.

[11] Seabra, Sergio H., Wanderley de Souza, and Renato A. Damatta.

[12] Buzoni-Gatel, Dominique and Catherine Werts.

[13] Däubener, Walter, Birgit Spors,Christian Hucke, Rüdiger Adam, Monique Stins, Kwang Sik Kim, and Horst Schroten.

[14] Barragan, Antonio, and L. David Sibley.

[15] Scheld, W. Michael, Richard J. Whitley, and David T. Durack.

[16] Scheld, et al.

[17] Enanga, B., R. J. S. Burchmore, M. L. Stewart, and M. P. Barrett.

 

[18] Enanga, et al.

[19] Enanga, et al.

[20] Scheld, et al.

[21] Peterson, Phillip K., and Jack S. Remington, eds.

[22] Enanga, et al.

[23] Peterson, Phillip K., and Jack S. Remington, eds.

[24] Scheld, et al.

[25] Peterson, Phillip K., and Jack S. Remington, eds.

[26] John, David T., and William A. Petri.

[27] Singh, Gagandeep, and Sudesh Prabhakar, eds.

[28] John, David T., and William A. Petri.

[29] Tato, P., A. M. Fernandez, S. Solano, V. Borgonio, E. Garrido, J. Sepulveda, and J. L. Molinari.

[30] White, A. C., Prema Robinson, and Raymond Kuhn.

[31] Del Brutto, Oscar H., Julio Sotelo, and Gustavo C. Roman

[32] John, David T., and William A. Petri.

[33] Pardridge, William M.