African Trypanosomiasis: a parasitic disease of the CNS

Introduction

Magnified 20,000X, this colorized scanning electron micrograph (SEM) depicts a grouping of methicillin resistant Staphylococcus aureus (MRSA) bacteria. See PHIL 617 for a black and white view of this image. Phoro credit: CDC.

By Maeve McLaughlin

Human African Trypanosomiasis (HAT) informally known as African Sleeping Sickness is an infection directly linked to a microscopic parasitic species known as Trypanosoma brucei. T. brucei are members of the Trypanosoma genus as well as the Trypanosomatidae family of unicellular parasites [3]. HAT is an extremely rare disease in the United States with fewer than 1,000 cases per year, but has a history of epidemics in Sub-Saharan regions of Africa [1]. There are a number of species of trypanosomes but only 2 have been known to infect humans, those being T.b gambiense and T.b rhodesiense [1].

Its transmission occurs through the tsetse fly, a member of the Glossina genus, only found in regions of Sub-Saharan Africa [1]. A bite from the infected species enters the human bloodstream, allowing the parasite to colonize areas up through the lymph nodes. Once infected, the spread of the disease easily develops into the central nervous system working its way to the brain. There are two main stages early and late, the late stage results in neurological defects. Early symptoms commonly consist of headache, fever, rash, or drowsiness [1].

Infected hosts may experience differences in circadian rhythm, insomnia, drowsiness throughout the day, and eventually potential death if left untreated [1]. Those in late stages of the disease experience disturbances in their circadian rhythm, insomnia, or other psychological symptoms such as dementia, depression, mania, irritability, or memory loss [1]. If left untreated, almost all patients are left in a coma, often resulting in death.

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Trypanosoma Brucei

Trypanosoma brucei are an extracellular protozoan flagellate parasitic species belonging to the Trypanosoma genus, residing mainly in Sub-Saharan regions of Africa. T. brucei are frequently located extracellularly in blood and tissue regions of the mammalian host, transmitting via leech or arthropod vectors [3]. There are 3 subspecies of T. brucei, yet only 2 species, T. b. gambiense (Tbg), T. b. rhodesiense (Tbr) cause infection in humans [2]. In general, T.brucei has a larger genome than most bacteria, and is a motile bacteria.

The genome of T.brucei is 26 Mb, contains roughly 1700 variant surface glycoproteins along with around 900 pseudogenes [11]. Genome analysis has shown horizontal gene transfer allows for increased metabolic properties for trypanosome parasites [11]. T.b. gambiense is the strain mainly responsible for human infection, accounting for 98% of all diagnosed cases of african trypanosomiasis [3]. This strain is also responsible for retaining the majority of the genetic information with a smaller genome.

Virulence Factors

There are a number of cellular mechanisms, structures, and molecules that allow for full parasitic function of trypanosomes. Regarding immune response, T. brucei parasites are capable of invading a host's immune system through the use of a variable surface glycoprotein (VSG) [7]. VSGs aid in protecting these parasites from lytic factors, ultimately evading the natural host immune response. As infection is prevalent, gene conversion between VSGs occurs at the trypanosome expression site [8]. This is considered an antigenic variation which enables the parasite to avoid the body's immune response as well as continue infection throughout the host. This constant switching also has made it challenging for clinicians to develop a vaccine that trypanosomes cannot evade.

Another strategy to evade immune response is through production of serum resistance associated proteins (SRAs) [7]. SRAs are unique to T.b rhodesiense and considered members of VSGs. They are exported to the flagellar pocket of trypanosomes before getting taken up by extracellular vesicles [12]. Serum resistant forms of T.b rhodesiense express and mRNA encoding protein, associated with surface glycoproteins [12]. Presence of SRAs aid in the survival of parasites, elongating the length and path of infection in a host. SRAs have the potential to evade cell lysis, preventing the breakdown of any present trypanosomes.

An important mechanism of T. brucei parasites is their flagellum. The flagellum is essential for parasite motility, pathogenesis, transmission of infection as well as immune evasion. Their flagellum is surrounded by its own membrane and attaches by length to the trypanosome cell body [10]. This wrap-around is vital for trypanosomes to invade other tissues throughout the body, given its extracellular characteristics. Moreover, T.brucei contain a flagellar pocket which is essential for the export of VSGs to other tissues throughout the body as well as the protection of extracellular macromolecules from the host’s immune response [10]. The flagellum oversees host cell attachment through attachment plaques, allowing parasites to develop a VSG coat [10]. Once coated, parasites are released into salivary glands, unleashing infection within the host.

Epidemiology

African Sleeping Sickness, or HAT infection is limited to regions of Sub-Saharan Africa specifically. There are two strains of Trypanosoma that infect humans, each infecting separate regions of Africa. T.b. gambiense, is centered in Central and West Africa while T.b. rhodiense is found in the southern and eastern portions of Africa [3]. Poor and rural communities face an increased risk due to frequent interaction with the land and water which are breeding grounds for bacteria.

Previous epidemics of Human African Trypanosomiasis have been documented in Uganda, Congo, and Cameroon, all of which are located in Central Africa [3]. As of late, most reported cases of T.b gambiense are found in the Democratic Republic of Congo and continue to decrease at a steady rate, hovering in the low thousands [8]. Popular tourist destinations such as Kenya, Malawi, Uganda, and Zambia may also notice an increase in T.b. rhodesiense cases due to constant visitation [3]. Travelers still face an increased risk of possible infection, especially those staying in areas of wildlife and nature preserves.

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Symptoms

Human African Trypanosomiasis is commonly distinguished between two stages, hemolymphatic and neurological [2]. The hemolymphatic stage falls under a “stage one” diagnosis where the parasite has yet to cross the blood-brain barrier, infiltrating the CNS. The neurological stage is considered “stage two” and occurs once the parasite has colonized within the CNS. T.b gambiense is known to take longer to work its way through the host, sometimes taking months to progress into the latter stages of the disease. T.b rhodisiense, which only occurs in about 2% of HAT cases, spreads its infection much quicker and can develop into the neurological phase within 1-2 weeks [1].

Beginning symptoms to those who are infected by the Trypanosoma brucei parasite may be considered moderate such as itching of the skin, low-grade fever, facial swelling, or headache. The development of a chancre, a specific type of skin lesion, is a common initial symptom. Swollen lymph nodes are another sign that that parasite is working its way towards the central nervous system [2]. If left untreated for an extended amount of time,infected patients may begin to experience neurological symptoms such as trouble sleeping, irregularities in circadian rhythm, and nocturnal insomnia [1]. Patients in the second stage of HAT may experience cognitive troubles including, but not limited to, memory loss, dementia, depression and mania, increased irritability, and mood swings [1]. Other neurological symptoms include severe dehydration, tremors in the hands, muscle and motor weakness, along with a potential for slurred speech [3].

In regards to gender, females may experience inconsistent patterns in their menstrual cycles, while men may be more prone to erectile dysfunction [2]. Majority of those infected are unaware until they begin to experience neurological symptoms, the second stage of HAT which can range, taking anywhere from weeks to months to transpire. Rate of infection varies on the host however, if left untreated both T.b. gambiense and T.b. rhodesiense can be fatal, ending in death.

Pathogenesis

Path of Infection

African Trypanosomiasis infection first stems from a bite of the tsetse fly, a member of the Glossina genus. The T.brucei parasite lives in the salivary glands of the glossina species.

Tsetse flies only become infected with T. brucei when trypanosomes are ingested in a blood meal of another species [3]. After ingestion takes place, trypanosomes undergo a series of physical changes until they arrive at the salivary glands. The trypanosome cell develops into its infective metacyclic form which is considered to be its proper form [3]. Eventually, when the saliva of a tsetse fly comes into contact with the host epithelium, it inserts its infected trypanosome cells into the human bloodstream. This contact induces stage one symptoms of sleeping sickness.

Infection first arises in the skin giving off the appearance of a chancre. As trypanosomes multiply, they are able to extend infection via lymph and blood cells to essential organs [3]. Once the parasite is able to reach up through the lymph nodes, the infection spreads all through the host, colonizing in the central nervous system [1]. As the disease works its way through the host, it compromises the strength of the blood brain barrier of the CNS, resulting in a decline in various neurocognitive functions. In rare cases, transmission of the parasite may occur sexually, or through blood transfusions but only few have been reported[5].

Impact on the Central Nervous System

The central nervous system is composed of the spinal cord and the brain. The CNS contains cerebrospinal fluid acting as a barrier between these to protect the brain and cord from any major damage or potential injury. The blood-brain barrier is another semipermeable membrane between the brain and the blood, an important barrier in T.brucei parasite infection. It is still unclear as to how trypanosomes are able to penetrate the blood-brain barrier of the CNS as it has proven to be resistant to microbes. One possibility is penetrability through barrier inflammation when trypanosomes are present [7]. Trypanosomes are also thought to enter via the choroid plexus, a network of various blood vessels in the ventricles of the brain. Trypanosomes have the potential to damage the choroid plexus, allowing parasites to penetrate the ventricles, up through the blood-barrier region [1]. Entry into the blood-barrier region can induce a variety of neurological symptoms in those who have been infected by T.brucei parasites. Infection of the CNS ultimately establishes a slow demyelinating process which, unless treated, will result in death of the infected patient [1].

References

Authored for BIOL 238 Microbiology, taught by Joan Slonczewski,at Kenyon College,2024