We give a highlight of common neglected tropical diseases in Uganda and East Africa region. Compiled by me (Dr.Keneth Kananura, MBChB,Mak) and my supervisor, Dr. Moses Egesa, PhD-MRC-Uganda)

1. Neglected Tropical
Diseases & Mucosal
Immunity
Student: KANANURA Keneth (SHO)
Facilitator: Dr. Moses Egesa, PhD

2. Introduction
● “Diverse group of communicable diseases that prevail in tropical &
subtropical conditions, affecting >1 billion people & cost developing
economies billions of dollars every year” WHO 2020
● Neglected Tropical Diseases (NTDs) are chronic infections
● Affect the poorest people of the world, living in sub-Saharan Africa,
Asia, & Latin America
● 40% of those affected live in Africa

3. Why study NTDs?
● They are preventable and treatable diseases
● They affect the poorest communities & keep them in poverty
● They disfigure and disable, keep children out of school & parents out of work
– limiting their potential; stigma, discrimination
● Don’t attract funding like the “big three” (HIV/AIDS, TB & Malaria)
○ $100 million in the United States in 2016 vs. $1.5 billion for HIV, malaria, &TB combined
● Universal Health Coverage cant be realized without beating NTDs

4. WHO List of 20 NTDs
Comprise of parasitic, bacterial, fungal and viral diseases

5. NTDs common in Uganda
Kolaczinski et al NTDs & their control in Ug 2006

6. Helminthic NTDs

7. Schistosomiasis
● Affects 250 million people
worldwide
● >92% of the cases in sub-
Saharan Africa
● Most human schistosomiasis is
caused by S haematobium, S
mansoni, and S japonicum.
● Less prevalent species, S
mekongi and S intercalatum, may
also cause systemic human
disease.
● Snail hosts for different spp
McManus et al. Nat Rev Dis Prim 2018

8. Schistosomiasis in Uganda
1Performance Monitoring and Accountability Schistosomiasis 2020
Brief 2017
2GAHI (Global Atlas of Helminths Infections)
• About 1 in 3 people is infected1
• In hotspots, prevalence >50%2
• Mainly caused by the helminth
Schistosoma mansoni
• Blood fluke, a trematode that
dwells in human veins
flattened body,
digestive tract
has a single opening

9. Ross AG et al. N Engl J Med 2002
ova
miracidium Fresh water snail
(Biomphalaria spp.)
Requires two hosts (snail and man)
Life cycle

10. Clinical manifestations
● Acute disease
○ a few hours; a rash or itchy skin (cercarial dermatitis)
○ within 3-8 weeks ; fever, chills, cough, arthralgia, myalgia (Katayama fever)
● Chronic disease
○ after years of infection, inflammation or scarring damages liver or intestine, pain,
anorexia, diarrhea, bleeding, polyps, strictures
○ Genito-urinary schistosomiasis: terminal hematuria, dysuria, bladder polyps;
lesions on vulva, vagina, cervix
● Ectopic disease
○ eggs in the brain, spinal cord, lungs, skin
○ cause Neuroschistosomiasis: seizures, paralysis, or spinal cord inflammation,
lower motor dysfunction, bladder paralysis, bowel dysfunction
○ Pulmonary complications: pulmonary HTN, cor pulmonale

11. Pathophysiology
● In general, clinical disease is caused by the host immune
response to migrating eggs
● Migration of eggs through tissues can be associated with
entrapment, inflammation, and subsequent fibrosis
● Eggs are carried via the splanchnic venous system and
may embolize to the liver, lungs, spleen, brain, or spinal
cord

12. Immunology
● Skin schistosomula vulnerable to killing by host
immune responses through complement
fixation and antibody (IgE, IgA & IgG)‐dependent
cell‐mediated cytotoxicity (Egesa, et al, 2018)
Egesa et al., Trends in Parasitology 2017
Schistosome eggs induce mainly Th2 responses
leading to an eosinophilic granulomatous reaction
involving T cells, macrophages, and eosinophils that
results in clinical disease

13. Nutman. Parasite
Immunol. 2015
Penetration
Migration and
maturation
Egg
Deposition
Chronic phase
Inflammatory Th1 dominate
Th2, IgE,
IgG4
Immunomodulation
Tregs, AAMs
Immunology

14. Investigations & Treatment
● Kato-Katz method/ Urine Filtration method
● PCR assay for Schistosome DNA
● POC circulating cathodic antigen (CCA)
● Tests for complications
Treatment:
● Praziquantel 40 mg/kg/day ( 2 divided doses for 1 day)
● combination of artemether & praziquantel can kill schistosomula during the
first 3 weeks of infection

15. Soil-transmitted helminths
● A group of diseases caused by the intestinal worms (nematodes)
○ Ascaris lumbricoides (roundworm),
○ Trichuris trichiura (whipworm),
○ Ancylostoma duodenale and Necator americanus (hookworm), and
○ Strongyloides stercoralis (threadworm)
● More than 1 billion people are at risk of STH
● Prevalent worldwide & a public health problem in 106 countries
● Global burden estimated at over 5 million DALYs, largely due to anemia,
stunting, & impaired cognitive development
slender,
unsegmented,
cylindrical
bodies

16. Clinical
manfestns
Ascaris lumbricoides Trichuris trichiura
hookworm Strongyloides stercoralis

17. Diagnosis
● Microscopic examination of fecal samples for
helminth eggs
● WHO recommends using the Kato–Katz method
● Three levels of intensity based on the number of
eggs per gram of feces (epg)
○ light, moderate, and heavy
○ Higher egg counts means more intense worm burdens,
associated with greater morbidity

18. Pathophysiology – Ascaris
● A lumbricoides can cause a type-1 hypersensitivity reaction to larval
stages (Loeffler syndrome), & adult worms can cause intestinal
pathology
● Adult Ascaris can lead to small bowel obstruction, volvulus, or
intussusception, especially in children, or
● can invade orifices leading to appendicitis, cholecystitis, pancreatitis,
and gastric ascariasis
● Pathology is positively related to worm burden, although non-linearly.

19. Pathophysiology
Endoscopic images of intestinal Ascaris lumbricoides and hookworm co-infection (A), Trichuris trichiura
infection (B), and hookworm infection (C)

20. Onchocerciasis
● Caused by the filarial nematode Onchocerca volvulus
● Blackfly (Simulium spp.),) the vector, breeds near streams & rivers
● Highly endemic in the West Nile region, along the central shores of Lake
Albert and in selected foci in SW Uganda.

21. Onchocerciasis
● Adult nematodes live in
subcutaneous nodules &
produce microfilariae, which
preferentially reside in the skin
and eye.
● Repeated exposures to infected
flies increase the number of
adult worms and microfilariae in
the host.

22. Clinical features
● Chronic cutaneous Onchocerciasis:
pruritus, papular rash, scarring, and lichenification.
Patchy depigmentation on the legs leads to a condition known as leopard skin
● Chronic ocular Onchocerciasis: may lead to sclerosing keratitis and
iridocyclitis, and finally to blindness.
Note: O. volvulus adults & microfilariae harbor endosymbiotic Wolbachia
bacteria.

23. Leopard skin & onchocercoma

24. Complications
● “River Epilepsy” : nodding syndrome and epileptic seizures
● Blindness
Investigations
● demonstration of microfilariae in a skin-snip biopsy sample
● Antigen testing(Oncho-27 antigens)
● PCR on skin snip samples
Treatment: Ivermectin (150mcg/kg), Moxidectin (WHO 2018 approval)

25. Immunology of filarial infection
Metenou and Nutman Front. Immunol.,2013

26. Bacterial NTDs

27. Buruli ulcer
● Buruli ulcer is a disabling skin infection caused by Mycobacterium ulcerans
● Generally begin as a painless dermal papule or nodule, progresses to form
an extensive necrotic ulcer with undermined edges.
● It primarily affects children aged 5-15 years.
● Transmission of the organism is probably via skin trauma
● M. ulcerans produces toxins, mycolactones (A,B,C, D)- responsible for its
pathogenesis.
● Its effects include cell structural deformation and apoptosis of several cell
types including immune cells.

28. Management
● Investigations: Direct microscopy,
PCR, Culture, histology
● Treatment: relies on timely & accurate diagnoses.
Antibiotics alone are adequate in early disease (Rif & Clarithromycin)
Surgical debridement, skin grafts, extensive wound care, & physical therapy
may be needed if treatment is delayed.

29. Trachoma
● Trachoma is the leading infectious cause of blindness worldwide.
● It is a chronic keratoconjunctivitis caused by recurrent infection
with Chlamydia trachomatis ( serotypes A,B,Ba & C)
● C trachomatis can be spread by either direct contact with an infected
person's eyes or nose or indirect contact, such as via contact with clothing
or flies that have come into contact with an infected person's eyes or nose.
● Poor sanitation, crowded living conditions, and insufficient clean water and
toilets can also increase the spread of trachoma.

31. Management of trachoma
● Diagnosis is clinical in endemic areas
● Treatment is based on WHO “SAFE” strategy
 S=surgery by ophthalmologist
 A=Antibiotics (oral azithromycin & tetracycline eye ointment)
 F= Facial cleanliness through health education & promotion
 E= Environmental improvement (personal & community hygiene)

32. Protozoal NTDs

33. Human African Trypanosomiasis (HAT)
● Vector-borne parasitic disease ttransmitted by tsetse flies (Glossina Spp)
● Caused by two subspecies of the single-celled parasite Trypanosoma
brucei:
○ T. b. rhodesiense found in eastern and southern Africa (“East African sleeping
sickness”, with reservoirs in livestock and wildlife (primarily a zoonosis), acute
form of disease with rapid progression to late stage
○ T. b. gambiense found in central and western Africa (“West African sleeping
sickness”, which causes the majority of human cases with the main reservoir
being human, a more chronic progressing more slowly

34. Human African Trypanosomiasis (HAT)
● The third subspecies T. b. brucei is a parasite primarily of cattle and
occasionally other animals, and under normal conditions does not infect
humans.
● Uganda has both gambiense and rhodesiense HAT, but in different zones

36. Clinical manifestations of HAT
Stage 1: Hemolymphatic stage
● Painful skin chancre
● Intermittent fever, general malaise,
myalgia, arthralgias, and headache
● Generalized or regional
lymphadenopathy, e.g.
"Winterbottom's sign“
● Edema
● Weight loss
● Organomegaly- splenomegaly
Stage 2: meningoencephalitic stage
● Persistent headaches
● Daytime somnolence followed by
nighttime insomnia
● Behavioral changes, mood swings,
or depression & Psychosis
● Seizures (more common in children)
● irritability, tremors, increased muscle
tone, ataxia, & hemiparesis
● Stupor and coma

37. Immunology
● Trypanolytic activity of apolipoprotein L-I (APOL1) in human serum protect
against T. b. brucei
● T. brucei can evade host immune response by antigenic variation by
switching most abundant surface protein VSG (variant surface glycoprotein)
● Antigenic variation leads to nonspecific polyclonal B cell activation during
infection & immunoglobulin (Ig)M is produced in large quantities
● There is immune complex formation & hyperplasia of RES esp spleen &
nodes.
● This may result in downregulation of immune system esp in advanced
disease.

38. Trypanosome-
host
interactions
Magez et al., Front. Immunol., 2020

39. Management
● Definitive diagnosis of T brucei infection requires actual detection of
trypanosomes in blood, lymph nodes, CSF, chancre aspirates, or bone
marrow.
● Card agglutination test for trypanosomiasis (CATT)

40. Leishmaniasis
● Caused by the protozoan Leishmania parasites (>20 spp) which are
transmitted by the bite of infected female phlebotomine sandflies (>90 spp)
● 3 main forms of leishmaniases
○ visceral (also known as kala-azar, which is and the most serious form)
○ cutaneous (the most common), and
○ Mucocutaneous
● linked to environmental changes such as deforestation, building of dams,
irrigation schemes, and urbanization

41. Visceral Leishmaniasis
● Aka kala-azar, is caused by Leishmania donovani & L. infantum
● Fatal if left untreated in over 95% of cases.
● Characterized by irregular bouts of fever, weight loss, enlargement of the
spleen and liver, and anaemia
● Most cases occur in Brazil, in India and East Africa
● Endemic in Pokot county in Uganda - First described in 1946

42. PKDL and Leishmania-HIV co-infection
Post-kala-azar dermal leishmaniasis (PKDL)
● PKDL is usually a sequel of visceral leishmaniasis that appears as macular,
papular or nodular rash usually on face, upper arms, trunks and other parts
of the body
Leishmania-HIV co-infection
● coinfected people have high chance of developing full-blown clinical
disease, and high relapse and mortality rates.
● ARVs reduce development of disease, delay relapses and increase the
survival of coinfected patients

43. Clinical manifestations
● Darkening of the skin
● Pentad of fever, weight loss, hepatosplenomegaly, pancytopenia, &
hypergammaglobulinemia
● Lymphadenopathy may be observed in E. African VL but is rare outside this
region
● Late disease; hepatic dysfunction, jaundice, and ascites can occur.
● Disseminated intravascular coagulation (DIC) is a rare but potentially lethal
complication of VL

44. Immunology
● Leishmania invade & replicate within host macrophages, evading innate and
cell-mediated immune responses
● Evasion & persistence are achieved through a combination of strategies
including; -neutralization of complement components,
-preventing release of macrophage superoxide & NO,
-suppressing induction of antigen-specific CD4+ T helper lymphocytes

45. Management of Leishmaniasis
● Definitive diagnosis of VL requires the demonstration of parasite
(amastigotes) by smear or culture in tissue (bone marrow or spleen).
● Treatments may include;
○ Antiparasitic pentavalent antimonial agents or
○ Liposomal amphotericin B or
○ Pentamidine

46. Viral and Other NTDs

47. Dengue
● It’s a mosquito-borne viral infection; caused by dengue virus (4 serotypes)
● Vectors: Aedes aegypti and Aedes albopictus
● Transmission to humans is by bites from infected female Aedes mosquitoes
● Clinical features: high fevers(40°C), pain behind eyes, headache, myalgia,
arthralgia, N+V, rash
● Severe dengue: bleeding tendency, circulatory failure, shock
● Lifelong immunity is attained after recovery to that serotype
● ℞: supportive mgt

48. Snakebite envemoning
● Caused by a bite or spit from a venomous snake
● About 5.4M snake bites occur annually resulting in 1.8-2.7M poisoning
cases
● Tropical regions of Asia & Africa are affected most
● High risk groups: rural agricultural workers, herders, children, hunters, etc
● Symptoms: paralysis, bleeding disorders, local tissue destruction, kidney
failure
● ℞ : Snake antivenom (EchiTAbG®)
WHO (2019), snake envenoming Harrison,et al, 2009,snake env. PLoS NTD 3(12):e569

49. Mucosal Immunity

50. Regional immune systems
● Include the mucosal immune systems, which protect the gastrointestinal,
bronchopulmonary, & genitourinary mucosal barriers, and the cutaneous
(skin) immune system
● Share a basic anatomic organization
○ Outer epithelial layer that prevents microbial invasion,
○ Underlying connective tissue (dermis and the lamina propria) containing
various cells types that mediate immune responses to organisms that
do invade through the epithelium,
○ Local or more distant draining secondary lymphoid tissues where
adaptive immune responses to invading microbes develop

51. Regional immune systems
● Contain specialized cell types & molecules that may not be abundant in
other sites
○ DCs (e.g., Langerhans cells in the skin), antigen transport cells (e.g., M cells in the gut), T
lymphocytes (e.g., γδ T cells in epithelia)
● Effector lymphocytes generated in draining lymph nodes or MALT of a
particular regional immune system (e.g., skin, small intestine) will enter the
blood and preferentially home back to the same organ (e.g., dermis, lamina
propria, respectively)

52. Immunity in the GIT
● The GI immune system is the largest & most complex.
● The intestinal epithelial barrier is formed by monolayer of epithelial cells,
interconnected with tight junctions & are covered with mucus and
bactericidal peptides
● Innate immunity is by macrophages that are localized in lamina propria; they
are phagocytic and bactericidal without secreting cytokines
● Dendritic cells are able to endocytose bacteria & also induce IgA response
● Adaptive immunity: Plasma cells secrete IgA2 that binds microorganisms &
intraepithelial lymphocytes that are cytotoxic
Schenk et al (2008) Mucosal imm. syst. GI Sci. Dir. 22(3) 391-409

53. Diseases Related to Immune Responses in the Gut
● Inflammatory Bowel Disease
○ Two main types: Crohn’s disease and ulcerative colitis
○ Defects in innate immunity to gut commensals microbes.
○ Abnormal Th17 and Th1 responses
○ Defective function of regulatory T cells
● Celiac Disease (gluten-sensitive enteropathy or nontropical sprue)
● Food allergies

54. Immunity in the respiratory tract
Akiko et al(2017); Nat Rev immunol;17(1):7-20

55. Diseases Related to Immune Responses in the respiratory tract
● Asthma
● COPD
● Allergic rhinitis

56. Skin immune system
● As primary immunological barrier to external env’nt, the skin is rich in
immune cells
● Epidermis has keratinocytes which provide physical barrier, produce
antimicrobial peptides(β-defensins)
● Keratinocytes express pattern recognition receptors(PRRs) which can
detect invading microorganisms
● Epidermis has Langerhans cells which express PRRs to initiate early
immune responses
● Dermis has immune cells like DCs, Mφ, mast cells, B & T cells, plasma cells

57. Diseases Related to Immune Responses in the skin
● Psoriasis
○ a chronic inflammatory disorder characterized by red scaly plaques,
○ caused by dysregulated innate and T cell–mediated immune responses
triggered by various environmental stimuli
● Atopic dermatitis or eczema
○ a chronic inflammatory, characterized by itchy rashes,
○ driven by type 2 innate and adaptive immune responses (ILC2 and Th2
cells) to epithelial damage and environmental antigens

58. Immunity in Genito-urinary system
● Innate immune cells(Mø, neutrophils, mast cells, NK-cells) rapidly respond &
evoke robust immune response during UTI
● Adaptive responses part. in the bladder are limited or absent due to IL-10
● Immune system differs btn lower & upper female reproductive tract (FRT)
● Immune system in vagina allows growth of beneficial microbes while
preventing that of pathogens
● Immune system in the uterus allows the fetus but eliminates pathogens
● The immune system changes with menstrual cycle & pregnancy
Soman & Yuxuan(2015);Nat Rev Immunol; Monin et al (2020);immu resp in hum FRT

59. Diseases Related to Immune Responses in the
Genito-urinary system
● Nephrotic syndrome-glomerulonephritis,
● Lichen sclerosus (affects anogenital area)

60. Immune privileged organs
● Tissues have evolved to be protected, to a variable degree, from immune
responses
● Operationally defined as sites where foreign tissue grafts can survive for
extended, often indefinite, periods of time whereas similar grafts placed at
regular sites in the body are acutely rejected.
● These organs include the eye, brain, pregnant uterus, testis.
● Immune privilege is thought to be an evolutionary adaptation to protect tissues
that are indispensable, yet have limited regeneration capacity from potentially
damaging effects of an uncontrolled inflammatory immune response
Medawar,1948; Streilein,2003; Niederkorn,2006

61. Immune privilege
● Foreign antigens that would evoke an immune response in most tissues are
often tolerated in these immune-privileged sites.
● The mechanisms underlying immune privilege vary between these tissues
and are not fully understood
● It is now increasingly accepted that the privileged status is preserved by
local active mechanisms that suppress responses to antigens within the
privileged tissues

62. Immune privilege…
● The Eye
○ Vision, which is essential for the survival, can be easily impaired by
inflammation
○ Evolved mechanisms that minimize the likelihood of immune responses
and inflammation
○ Anatomic features of the anterior chamber that contribute to immune
privilege include
■ the tight junctions of the epithelial layer & resistance to leakiness of
blood vessels in the tissues adjacent to the anterior chamber (the
so-called blood-eye barrier)

63. Immune privilege…
● The Testis
○ Immune privilege serves to limit inflammation that may impair male
fertility
○ Like the eye & brain, has a blood-tissue barrier that limits delivery of
cells & molecules to the sites of spermatogenesis.
■ barrier is formed by Sertoli cells, lining outer layer of seminiferous
tubules where spermatogenesis takes place.
○ The hormonal milieu of the testis, rich in androgens, has an anti-
inflammatory influence on macrophages.
○ TGF-β is produced by Leydig, Sertoli, and peritubular cells and likely
contributes to local immune suppression.

64. Immune privilege…
● The Brain
○ Inflammation in the brain can lead to functional derangement & death of
neurons, with disastrous consequences
○ Anatomic features impair initiation of adaptive immunity to antigens
include
■ a scarcity of DCs, and
■ the nature of the tight junctions between brain microvascular
endothelial cells (the so-called blood-brain barrier)

65. Immune privilege of the Mammalian Fetus
● Maternal immunological tolerance to the developing mammalian fetus,
which expresses allogeneic paternal antigens, depends on mechanisms that
act locally at the placental maternal-fetal interface
● Possible mechanisms include
○ lack of MHC expression on fetal trophoblasts,
○ the actions of Treg, and
○ the local IDO-mediated depletion of tryptophan needed for lymphocyte
growth and generation of a toxic by-product.

66. END
Thank you