Trypanosoma brucei

kinetoplastida · trypanosomatidae · flagellate · 15–30 µm

Extracellular blood parasite with a remarkable surface-coat switching mechanism (VSG) enabling indefinite immune evasion; invades the CNS in stage 2, causing progressive neuropsychiatric deterioration — the "sleeping sickness" syndrome.

Classification & Structure

Taxonomy	Kingdom Excavata → Phylum Euglenozoa → Class Kinetoplastea → Order Trypanosomatida → Trypanosoma brucei (complex)
Subspecies	T. b. gambiense (type 1 & 2) — 95% of HAT cases, chronic (months–years); T. b. rhodesiense — acute (weeks); T. b. brucei — animal-only (nagana)
Bloodstream form (BSF)	Slender trypomastigote, 15–25 µm; single flagellum; entirely covered by VSG coat (~10 million molecules); proliferating form found in blood and lymph
Stumpy form	Non-dividing, pre-adapted for tsetse uptake; elevated cAMP; expresses EP/GPEET procyclins; metabolically distinct from slender BSF
Procyclic form	Replicates in tsetse midgut; surface procyclin coat replaces VSG; undergoes developmental journey through fly to form metacyclic trypomastigotes
Variant Surface Glycoprotein (VSG)	~60 kDa GPI-anchored glycoprotein; dense surface coat protecting invariant proteins from antibody; ~2,500 VSG genes/pseudogenes; monoallelic expression from ~20 expression sites
Kinetoplast	Mitochondrial DNA network (maxicircles + minicircles); minicircle guide RNAs enable RNA editing of mitochondrial mRNAs — a trypanosome hallmark; target of some trypanocidal drugs
Glycolysosomes	Peroxisome-like organelles housing entire glycolytic pathway; BSF bloodstream forms lack functional mitochondrial oxidative phosphorylation and depend on glycolysis
Size / morphology	Trypomastigote: 15–30 µm × 1.5–3.5 µm; undulating membrane along flagellum; single posterior kinetoplast; single nucleus; single mitochondrion

Infection Mechanism & Pathogenesis

Tsetse inoculation & initial proliferation Infected tsetse fly (Glossina spp.) injects metacyclic trypomastigotes into skin during bloodmeal. Parasites differentiate into slender bloodstream forms, proliferate in subcutaneous tissue → lymph → blood. A local chancre (painless nodule) may form at the bite site within 1–2 weeks.
Stage 1 (haemolymphatic) disease Parasites circulate freely in blood and lymphatics. Fever, headache, lymphadenopathy (Winterbottom's sign — posterior cervical nodes), splenomegaly, hepatomegaly, anaemia, and periodic febrile waves tracking antigenic variation episodes. Host mounts antibody response clearing dominant VSG; rare switching variants expand, producing characteristic wave pattern.
VSG antigenic variation — indefinite immune evasion Each bloodstream trypanosome expresses a single VSG from one active Expression Site (ES). Stochastic ES switching occurs at rate ~10⁻⁶ per division. New VSG coat escapes existing antibodies; immune pressure selects switch variants. With >1,000 functional VSG genes and combinatorial mosaic VSGs, exhaustion of variants is essentially impossible.
Stage 2 (CNS) invasion & neuroinflammation Parasites cross blood–brain barrier (tight junction disruption, possibly CXCL10-mediated) and blood–CSF barrier into brain parenchyma and CSF. Perivascular neuroinflammation, astrocyte activation, demyelination, and disrupted sleep–wake regulation (suprachiasmatic nucleus / thalamus damage) cause the defining polyphasic sleep disorder, progressive encephalopathy, coma, and death if untreated.
Immunosuppression & immune complex pathology Massive polyclonal B-cell activation → hypergammaglobulinaemia with non-specific IgM; paradoxically, specific protective responses are suppressed. Immune complex deposition contributes to anaemia, thrombocytopenia, and renal pathology. VSG shedding and trypanosome lysis release trypanosomal products triggering inflammatory cascades.

Host Immune Response

Complement (early lysis) Macrophage activation TNF-α / IL-6 / IL-12 Neutrophil recruitment Anti-VSG IgM (waves) Anti-VSG IgG (clone-specific) T-cell activation B-cell exhaustion (polyclonal) T-cell anergy (chronic) VSG coat switching ES monoallelic expression Trypanolysis resistance (T. b. rhodesiense SRA gene)

Disease Spectrum

Condition	Stage / Form	Key Features	Severity
Haemolymphatic HAT	Stage 1, both subspecies	Fever, Winterbottom's sign, anaemia, hepatosplenomegaly; no CNS signs	Moderate
CNS sleeping sickness (gambiense)	Stage 2, chronic	Months to years after stage 1; sleep disorder, personality change, tremor, coma	Fatal untreated
CNS sleeping sickness (rhodesiense)	Stage 2, acute	Rapid progression weeks–months; cardiac involvement; CSF >5 WBC/µL or trypanosomes	Fatal untreated
Trypanosomicidal febrile episodes	Both stages	Each VSG switch wave cleared by host antibody → spike fever; repeated over months	Moderate
Post-treatment reactive encephalopathy (PTRE)	Stage 2, post-melarsoprol	5–10% on melarsoprol; acute encephalopathy; ~5% fatal; managed with prednisolone	Severe

Treatment & Prophylaxis

Fexinidazole (stage 1 & stage 2 gambiense) — first-line oral Nitroimidazole prodrug activated by trypanosome type 1 nitroreductase; active metabolites kill both bloodstream and CNS parasites. 10-day oral regimen; 94–98% efficacy in stage 1/2 combined; WHO-approved 2018. Replacing IV regimens. Contraindicated in stage 2 with >100 WBC/µL in CSF (use NECT).
NECT (Nifurtimox-Eflornithine Combination Therapy) — stage 2 gambiense Eflornithine (DFMO) irreversibly inhibits ornithine decarboxylase; nifurtimox generates reactive radicals. 7-day IV eflornithine + 10-day oral nifurtimox; replaces eflornithine monotherapy; >94% cure; WHO essential medicine.
Melarsoprol — stage 2 rhodesiense (last resort) Organoarsenic; inhibits trypanothione reductase; IV administration; 5–10% post-treatment reactive encephalopathy; only efficacious drug for T. b. rhodesiense stage 2. Being phased out where fexinidazole is applicable.
Pentamidine — stage 1 gambiense Diamidine antiprotozoal; inhibits kinetoplast DNA; IM injection; >93% efficacy in stage 1; does not cross BBB adequately; no CNS efficacy.
Suramin — stage 1 rhodesiense Polysulphonated naphthylurea; inhibits multiple trypanosome enzymes; IV; stage 1 T. b. rhodesiense only; renal toxicity monitoring required.
Vector control & surveillance Tsetse fly traps (tiny targets) and insecticide-treated targets; population-level screening (CATT card agglutination for gambiense); active case-finding; HAT global elimination target 2030. No vaccine; no chemoprophylaxis available.

Cross-Atlas Connections

Infects: CNS Infects: Blood Infects: Lymph nodes Damages: Blood–brain barrier Damages: Thalamus / hypothalamus Damages: Bone marrow (anaemia) Targets: Macrophages (evasion) Targets: B-cells (polyclonal activation) Vector: Glossina (tsetse fly)

References

Kennedy PGE (2013). Clinical features, diagnosis, and treatment of human African trypanosomiasis. Lancet Neurol 12(2):186–94.
Büscher P et al. (2017). Human African trypanosomiasis. Lancet 390(10110):2397–409.
Sokolova AY et al. (2010). Fexinidazole: A new oral nitroimidazole drug candidate for HAT. Antimicrob Agents Chemother 54(2):887–92.
Cross GAM (1990). Cellular and genetic aspects of antigenic variation in trypanosomes. Annu Rev Immunol 8:83–110.
WHO (2023). Trypanosomiasis, human African (sleeping sickness). Fact sheet. Geneva: World Health Organization.
Steverding D (2008). The history of African trypanosomiasis. Parasit Vectors 1:3.

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