-Both parasite cause babesiosis and plasmodiasis in humans and animals -Morphological semblance of both: B microti and P falciparum Of the phylum Apicomplexa Complex life cycles alternating in invertebrate (tick/mosquito) and vertebrate host (Marquardt et al., 2000) The infective stage is the sporozoites while the gametocyte is the reproductive stage Are obligate endoparasites and host infectivity is very specific

1. Department of Medical Microbiology and Parasitology,
College of medicine, university of Lagos
MIP 951 RESEARCH SEMINAR
PROPOSED TITLE: BABESIA WITH PLASMODIUM COINFECTION
SEMINAR 1: The biology of Babesia and Plasmodium parasites
SEMINAR 2: Ecological kinetics and immunology of Babesia with
Plasmodium co-infection
SEMINAR 3: Pathophysiology of Babesia and Plasmodium infection,
diagnosis and treatment
By
OROK, AKWAOWO BASSEY
1

2. SEMINAR 1:
The biology of Babesia &
Plasmodium parasites
2

3. OUTLINE
• Introduction
• Life cycle of Plasmodium and Babesia
• Epidemiology of Babesiosis and Malaria
• Babesia and Plasmodium in the phylum, Apicomplexa
• Host cell invasion by Plasmodium and Babesia
• Kinetic of Invasion
• Parasite Proteins that aid invasion
• Host cell receptor that aids parasite invasion
• Conclusion
3

4. Aim and objectives of the review
Specifically, this review will discuss:
• Biology and life cycle of Plasmodium and
Babesia
• Epidemiology of babesiosis and malaria
• Host cell invasion
• Parasite proteins and host cell receptors that
aid invasion
• Conclusion and References
4

5. Introduction
• Both parasite cause babesiosis and plasmodiasis in
humans and animals
• Morphological semblance
• Of the phylum Apicomplexa
• Complex life cycles alternating in invertebrate
(tick/mosquito) and vertebrate host (Marquardt et al.,
2000)
• The infective stage is the sporozoites while the
gametocyte is the reproductive stage
• Are obligate endoparasites and host infectivity is very
specific (Dessein et al., 2001)
5

6. Introduction Contd..
• Expression of specific proteins on merozoites is
critical to infection (Chitinis, 2001).
• These proteins initiate and aids RBCs attachment
and invasion (Lobo, 2005).
• Are key target vaccine candidates (Aikawa et al.,
1978).
• Vital role in protection, pathology of the diseases
(Angulo and Fresno 2000)
6

7. Differences between Babesia and Plasmodium
Babesia Plasmodium falciparum
A .Morphology
●Schizont /gametocyte
●Pigment formation
●Liver stage/ Hypnozoites
Absent
Absent
Absent
Present
Present
Present- P. ovale/P. vivax only
B. Vector Tick mainly Ixodidae Mosquito Anopheles types
C. Major species affecting man B. microti, B. duncani, B. divergens,
and B. venatorum
P. falciparum, P. ovale, P. vivax, P.
malariae
D. Protective mechanisms None Duffy blood group antigen, HbS or B-
Thalassemia- G6PD deficiency.
E. congenital infection unknown Common with falciparum malaria
F. Population at risk of infection >50 years, immunocompromised
individuals, lacking a spleen,
immunosuppressive drugs
Children below the age of five, pregnant
women, the elderly and the non-
immune
G. Laboratory diagnosis Giemsa stained blood smears, PCR,
Babesia IgM /IgG antibody
RDT by blood, urine, saliva and sweat ,
Microscopy + PCR
H. Treatment clindamycin + quinine + azithromycin ACTs, quinine etc.
I. Prevention Elimination of ticks in residential
areas
Use of LLIN, ITN,IRS , Prophylaxis,
etc 7

8. Similarities between Babesia and Plasmodium
Babesia Plasmodium falciparum
Sub-microscopic infection Common Common
Mode of transmission to
man
Vector borne
Tick,/blood transfusion
Vector borne, Anopheles mosquito,
blood transfusion
Ring-staged trophozoites Common to both Common to both
Intraerythrocytic nature Common to both Common to both
Clinical features Similar: Asymptomatic>>severe Similar: Asymptomatic>>severe
Infected erythrocytes undergo sequestration undergo sequestration
Shared clinical and
pathological features
Structural protrusion on IRBCs, re-
orientation of apical complex during
host cell invasion and cerebral
babesiosis
Structural protrusion on IRBCs, re-
orientation of apical complex during
host cell invasion and cerebral malaria
(Lau 2009)
Parasite factors that aid
pathogenicity
Multiplication rate
Invasion pathways
Cytoadherence
Antigenic polymorphism
Antigenic variation (VSAs)
(Miller et al., 2002)
Multiplication rate
Invasion pathways
Cytoadherence
Rosetting
Antigenic polymorphism
Antigenic variation (PfEMPs)
8

9. Trophozoites of Babesia parasites in human erythrocytes
• a) B. divergens, b) B. venatorum,
•c) B. divergens-like, Kentucky, d) B. microti, e) B. duncani, f)KO1,Korea.
•1.Paired piriforms; 2. Tetrads; 3.Ringforms.
•Source: Vannier and Krause 2009. 9

10. •Trophozoites of Plasmodium parasites, Pf similar to Babesia. Source WHO manual, 1991. 10

11. Babesia: Biology & Life cycle
• First discovered in 1888 by Victor Babes
• In 1893, Smith and Kilborne discovered the
vector» Ixodid ticks.
• Specifically, Ixodid ticks were found to be the
causative agent for bovine babesiosis caused by
B. bigemina and transmitted by cattle tick,
Boophilus microphilus.
• This revelation was first proof that an arthropod
was a vector of a diseases (Marquardt et al.,
2000).
11

12. Geographic distribution
• Is worldwide
• Little is known in malaria-endemic countries,
where misidentification occurs (Lobo et al., 2012)
• Is an important emerging tick-borne disease,
which causes major economic losses in domestic
animals (Bock et al., 2004)
• B. bigemina, B. bovis and B. divergens are mainly
the agents of bovine babesiosis (Uilenberg 1995)
• B. microti, B. duncani, B. divergens, and B.
venatorum infect humans (Vannier and Krause
2009)
12

13. Life Cycle
• Sporozoites are injected during the blood meal
• Invades RBCs, differentiate into trophozoites, which
divide asexually (budding) into 2 or 4 merozoites
(tetrad structure coined Maltese-cross form)
• Merozoites egresses the RBCs and invade new ones,
continue the replicative cycle
• A few merozoites stop division and transform into
gamonts or pregametocytes
• Gamogony and sporogony take place in the tick.
• When gamonts are taken up by a tick, they
differentiate in the gut into gametes, that fuse
forming a zygote ( gamogony).
13

14. Life cycle contd…
• Zygotes » motile kinetes »multiply by
sporogony=sporozoites »hemolymph, invading
several tick organs, e.g. salivary glands
• In some Babesia spp., sporozoites invades
ovaries and eggs, and infective sporozoites are
formed in larvae (transovarial transmission)
(Mehlhorn and Schein, 1984)
• Sporozoites invade the larvae »nymph » adult
(trans-stadial transmission)
14

15. 15

16. EPIDEMIOLOGY OF BABESIOSIS
• First human babesiosis was reported in a Yugoslavia
farmer, in 1957 (Tavassoli et al., 2013)
• In America, B. microti and the WA1 (Washington)
causes major infections (Dammin et al., 1981)
• In Europe, major infection is caused by B. divergens
• Determinant factors in the severity of the diseases
include: age, immunocompetence, and co-infection
of the tick with other pathogenic agents (Homer et
al., 2000)
• Information on humans is limited in Asia and Africa
16

17. Babesiosis in Nigeria
• In Nigeria, reports are from veterinary studies
• In one study (cattle),B. bigemina and B. bovis
accounted for 63.0% of the positive cases and Theileria
spp with 12% ( Kamani et al., 2010)
• In another, B. canis, 108 dogs tested, 11 were found to
be positive (Amuta et al., 2010)
• Human studies showed babesial antibodies in 94 (54%)
sera from 173 Nigerian males tested (Leeflang et al.,
2002)
• However, no correlation with livestock contact, malaria
parasitemia
• Babesia was not found in blood smears either
17

18. Host range
• Primarily infects mammals but also birds and reptiles (Bush et
al., 2001)
• The genus contains >120 species
• Bovines (B. argentina, B. bigemina, B. bovis, B. divergens, and
B. major)
• Ruminants (B. foliate, B. ovis, B. motasi, B. crassa, and B.
taylori)
• Horses and donkeys (B. caballi and B. equi)
• Pigs (B. perronciti, B. trautmanni)
• Dogs (B. canis and B. gibsoni),
• Felines (B. herpailuri, B. panthera, and B. felis )
• Lions (B. leo)
• Rodents (The Babesia microti group)
• Aves : About 14 species and B. shortii is the only one known
to be pathogenic (Peirce, 2000) 18

19. CLASSIFICATION
• Two genera make up the class; Piroplasmea.
• These are Babesia and Theileria (Marquardt et al.,
2000)
• The classical difference : absence of schizont in Babesia
• In the ticks, Babesia undergoes trans-stadially (from
larva to nymph) and trans-ovarially (from egg to larva);
is lacking in Theileria
• Babesia spp. are grouped into the small Babesia spp.
(1.0-2.5µm), which include B. gibsoni, B. microti and B.
rodhaini, and a large Babesia spp. (2.5-5.0µm) which
include B. bovis, B. caballi and B. canis.
• The small Babesia spp are more closely related to
Theileria spp with the exemption of B. divergens which
appears small on blood smears but is genetically
related to the large Babesia spp (Garcia, 2007)
19

20. Biology &Life cycle of Plasmodium
• Four distinct species infected humans: P.
falciparum, P. vivax, P. ovale and P. malariae
(WHO, 2010).
• In addition, P. knowlesi, a simian parasite, is able
to naturally infect humans (Singh et al., 2004)
• Its prevalence have been reported severally in
parts of Asia
• No report in Africa
• Spectrum of diseases presentation differs
20

21. 21

22. EPIDEMIOLOGY OF MALARIA
• First in terms of morbidity and mortality
• A subject of high research priority
• Worldwide prevalence of the diseases is
estimated to be in the order of 300 - 500 million
persons
• Is responsible for > 438,000 deaths annually
(WHO, 2015)
• More than 90% of all cases occur in Sub-Saharan
Africa where the ambient factors for parasite and
vectoral transmission are readily abound (WHO,
1998)
• Children < the age of five, pregnant women are
mostly at risk
22

23. Malaria in Africa
• Thirty countries account for 90% of global
malaria deaths.
• Nigeria, Democratic Republic of Congo (DRC),
Ethiopia, and Uganda account for nearly 50%
of the global malaria deaths.
• Malaria is the 2nd leading cause of death from
infectious diseases in Africa, after HIV/AIDS.
• Almost 1 out of 5 deaths of children under 5 in
Africa is due to malaria.
23

24. Malaria in Nigeria
• Is a major public health problem
• There are an estimated 100 million malaria
cases with over 300,000 deaths per year
• This compares with 215,000 deaths per year
from HIV/AIDS.
• Malaria contributes to an estimated 11% of
maternal mortality.
24

25. Epidemiological classification
• Hypoendemic malaria – Where children of 2-9
years of age have parasite rates of less than
10%.
• Mesoendemic malaria – Where children of 2-9
years of age have parasite rates of 11-50%.
• Hyperendmic –Where children of 2-9 years of
age have parasite rates of 51-75%.
• Holoendemic - Where children of 2-9 years of
age have parasite rates of more than 75%.
25

26. BABESIA AND PLASMODIUM IN THE PHYLUM APICOMPLEXA
• The name Apicomplexa is derived from two Latin
root words “apex” (top) and “complexus”
(infolds) and refers to the set of organelles at the
tip of the merozoite (Cowman and Crabb 2006)
• They are critically dependent on invasion of host
cell (Franssen et al., 2003)
• Parasite transmission between the host and the
vector follows a regular pattern (Cowman et al.,
2012)
• Three distinct secretory organelles: rhopteries
and micronemes (are always associated with
anterior end) and dense granules (in the
posterior end)
26

27. Diagram of Apicomplexan merozoite, highlighting major organelles and cellular structures (Cowman and
Crabb, 2006)
27

28. HOST CELL INVASION BY PLASMODIUM AND BABESIA
• The apical organelles are involved in
interactions between the parasite and the
host
• Serves as invasive aids into RBCs
• A number of host cell receptors and parasite
proteins (ligands) have been identified (Lobo
et al., 2012)
• Invasion of red cells marks a turning point in
the invasiveness and pathogenicity
28

29. KINETICS OF HOST-CELL INVASION
• Four distinct steps of invasion into host RBCs
• These are:
●(1) Initial merozoite binding
●(2) Re-orientation and RBC deformation
●(3) Junction formation
●(4) Parasite entry
These steps have been illustrated using electron
microscope ( Lobo et al., 2012)
29

30. • Kinetic process of invasion of RBC by merozoite. Source: Qiagen
sample and Assay Technologies, 2012 30

31. FACTORS THAT AID CELL INVASION
Broadly divided into 2:
Parasite proteins RBC receptors
31

32. PARASITE PROTEINS THAT AID CELL INVASION
• At the sporozoite level: circumsporozoite protein (CSP)
• At the merozoite level after egress: The merozoite surface
protein family (MSP), of which MSP1 is the most abundant
(Egan et al., 1996)
• Others proteins classified as:
→→adhesins that function as ligands binds directly to specific
receptors on the RBCs: EBP, PvDBP and RBP
→→invasins that function in the invasive process: AMA-1,
RAPs (RON2) (Cowman et al., 2012)
32

33. THE ADHESINS
• They belong to two protein families:
-- Erythrocyte binding-like (EBL) or Duffy binding like (DBL)
proteins
---Reticulocyte binding-like homologues (PfRh) located in
microneme and rhoptries (Bapat et al., 2011)
• The EBL (EBA-175, EBA-181 and EBA-140) and PfRh (PfRh1,
PfRh2a, PfRh2b, PfRh4 and PfRh5) families play a pivotal role
in entry process (Tham et al., 2012)
• Also, several Babesia molecules have been shown to bind
RBCs in vitro (Lobo 2005)
• In Babesia bovis, MSA-2 and RAP-1 (Lobo 2005)
• In Babesia equi, EMA-1 and EMA-2 (Kumar et al., 2004).
33

34. THE INVASINS
• Are proteins of the apical organelles
• Are concealed inside and selectively released
when encountering the host (Sibley, 2004)
• Are stored apically in micronemes and most of
them have been studied to be potential
vaccine candidates
• E.g. Apical membrane antigen 1 (AMA-1),
Rhoptry associated protein-1 and -2 (RAP-1
and RAP-2)
34

35. IMPORTANCE OF ADVASINS AND INVASINS
• MSPs as markers for identification of clones causing an
infection e.g. msp-1, msp-2, Glurp etc.
• Makes it possible to distinguish individual parasite
concurrently present in the blood sample
• Is important in tracing individual parasite clones in
population
• Allows for detailed study of infection dynamics in
ecological studies
• In drug therapeutic efficacy trial provides information
on the multiplicity of infections, re-infection and
recrudescence
• Aids in interventions and vaccine development (Felger
et al., 1999)
35

36. HOST RBCs RECEPTORS
• Majority of receptor-ligands have been identified (Cooke et
al., 2005)
• Glycophorin and complement receptor-1(CR-1) (Tham et
al., 2012)
• In general, glycophorin mediate interactions with EBL
adhesins; glycophorin A: EBA-175, glycophorin B: EBL-1,
glycophorin C: EBA-140 whereas CR-1 binds to PfRh4(Tham
et al., 2012)
• All glycophorin-EBL interactions are dependent on sialic
acid present on the erythrocyte receptor and not PfRh4-
CR-1interactions (Tham et al., 2010, 2011)
• Duffy blood group antigen/receptor for chemokines (DARC)
• In Babesia, there is paucity of information
• However, glycophorins A and B have been identified (Lobo,
2005)
36

37. Conclusion
• Babesia and Plasmodium parasites posses
intracellular lifestyle akin to other members of
apicomplexa
• This result in intimate and obligatory
relationship with the host
• Understanding the interactions will be helpful
in guiding appropriate treatment, care and
vaccine development.
37

38. Recommendations
• Prevention of tick & mosquito bite
• Development of potent transmission blocking
vaccines: e.g. Anti-CSP, Anti-adhesins, Anti-
invasins
38

39. SOME CITED REFERENCES
• Amuta EU, Atu BO, Houmsou RS and Ayashar JG. (2010).
Rhipicephalus sanguineus infestation and Babesia canis
infection among domestic dogs in Makurdi, Benue State-
Nigeria. International Journal of Academic Research. 3: 170-
172
• Chitnis CE. (2001). Molecular insights into receptors used by
malaria parasites for erythrocyte invasion. Current Opinion in
Hematology. 8: 85-91
• Cooke BM, Mohandas N, Cowman AF, Coppel RL. (2005).
Cellular adhesive phenomena in apicomplexan parasites of
red blood cells. Veterinary Parasitology. 132: 273–295
• Cowman AF and Crabb BS. (2006). Invasion of red blood cells
by malaria parasites. Cell. 124:755–766
• Lobo CA, Rodriguez M and Cursino-Santos JR. (2012). Babesia
and red cell invasion. Current Opinion in Hematology. 19: 170-
175.
39

40. SEMINAR II
ECOLOGICAL KINETICS AND IMMUNOLOGY OF
BABESIA WITH PLASMODIUM CO-INFECTION
40

41. Outline of presentation
• Introduction
• Ecology of concomitant infections
• Dynamics and kinetics of concomitant parasitic
infections
• Immunology of Babesia and Plasmodium in infected
host
• Immune kinetics of Babesia with Plasmodium
coinfection
• Conclusion
• References
41

42. Introduction
• A parasite refers to an organism that lives in or on
another organism, usually larger, from whom it
derives shelter, food (Fagbenro-Beyioku, 2011)
• Some causes chronic infection, visible after 10-20
years some noticeable within few weeks (Dessein
et al., 2001)
• In nature, poly-infection in a single host is a
common phenomenon (Cox 2001)
• A number of interactions are described
• Results in increased, suppressed infection (Cox
2001)
• Outcomes of interactions: is the host benefiting
or is affected?
42

43. Is the host benefiting? Samples!
• Trichinella spiralis in animals were refractory to subsequent
infection with Trypanosoma lewisi (Meerovitch and Ackerman,
1974)
• Monkey infected with B. microti (avirulent parasite) were shown
to be refractive to P. cynomolgi (van Duivenvoorde et al., 2010).
• Patients drug-cured for Babesia infection were shown to be
protected with subsequent challenge with Plasmodium (Cox and
Turner, 1970)
• Mice recovered from infections with B. microti were resistant to
challenge with P. vinckei (Cox, 1978)
• Mice pre-treated with killed Corynebacterium parvum were
shown to completely resistant to infection with B. microti or B.
rodhaini and were protected from P. vinckei or P. chaubaudi
infection (Clark et al., 1978)
• Mice given Bacillus Calmette-Guerin (BCG) were protected
against babesiosis (Clark et al., 1977)
43

44. Aims and objectives of the review
This will be addressed in 3 main thematic :
Ecological dynamics and kinetics of
concomitant infection
Immunology of Babesia and Plasmodium
Immune kinetics of Babesia with Plasmodium
coinfection
44

45. Ecology of concomitant infections
• One-Host-parasite interactions are rarely
seen
• Intra and inter- parasite species abound
• Understanding helps in epidemiology
• May create default in diagnosis
treatment (Adeoye et al., 2007)
45

46. Dynamics of concomitant parasitic infections
• The science of forces involved in propelling the
course of infection
• Antagonistic Effect (Suppressed infections or
growth and development of one or both parasites
e.g. direct competition, antigenic cross reaction,
immunopotentiation and possibly, harming the
host less)
• Synergistic Effect (Enhanced infection of one or
both parasites e.g. enhanced pathogenicity or
virulence or immunosuppression and possibly
harming the host more)
• Inconclusive: No observable effects on either the
parasites or the host (Ackerman, 1977)
46

47. Kinetics of concomitant parasite infections
• Interest in coinfection has increased
• In suppressive interaction:
A. The role of host genetic factors e.g. Rbcs
disorders
B. Role of certain pathophysiological properties e.g.
VSG, PfEMPI genes
C. Changes in host environment e.g. cytokines
D. Reactivity of the immune response e.g. early
polarization with cytokins
E. Cross immunity
47

48. Immunology of babesia in infected host
• Host immunity is thro episode of recovery from
infection or through immunization
• Th1 and Th2 cytokine pathways are activated to
control infections
• Humoral, cell-mediated innate immunity are
involved
• Monocytes, lymphocytes and protective
antibodies induced by helper T cells activity
(Valentin et al., 1993)
• Subsequent events determines series of activity
in the cytokine network
48

49. A B C
Establishment Progression Resolution
Phase Phase Phase
IgG controls IFN-γ, TNF-α, NO, ROS, NK-cells T- cell controls infection.
and
infection. Activated macrophages (Mφ)
controls infection.
FIG I:
Theoretical model showing sequence of infection from establishment phase, initiation phase and
resolution phase.
Source: Homer et al., 2000.
49

50. Immunology of plasmodium infection
• Host Immunity to infection is mainly at the blood stage of
the parasite
• The sporozoites stage rarely provokes immune response.
• Both cell-mediated and antibody-dependent immunity are
involved (Angula and Fresno, 2002)
• Adaptive immune response viz:Th1-Th2 paradigm
produces various signature cytokines (IFN-γ TNF-α, β) that
mediate parasite clearance
• Th1 cells and derivatives are important in cellular
immunity
• Over-exuberant pro-inflammatory activities cause tissue
damage and immunopathology
• Th2 cells and its derivatives (IL-2, IL-4, IL-5, IL-9, IL-10 and
IL-13) mediate humoral immune response (Wan, 2010)
50

51. Figure II. Antigen on APC binds to activate cytokines (Cox
and Wakelin, 1999).
51

52. Immunoregulation
IL-10
IL-4
IFN-
γ
IL-1
IL-2
IL-2
IL-1
Macrophage
B
cell
NK
Th2
APC
Tc
Th1
Th2 cell products IL-4 and IL-10 inhibits Th1
response.

53. IMMUNOLOGY OF BABESIA WITH PLASMODIUM CO-INFECTION
• Concomitant infection might impose
conflicting selective pressure upon Th cell
response
• Parasites that share the same Th response
optima might lead to response synergies
(Graham, 2002)
• Host immune response to malaria and
babesiosis are similar
• Activation of macrophages forms the basis of
protection in both (Stich et al., 1998)
53

54. Babesia with Plasmodium coinfection
Result in:
• Suppression of growth and cross protection of
infected host (van Duivenvoorde et al., 2010)
Likely Factors of suppression
• The role of Pro-inflammatory cytokines
• Effect of IFN-γ and TNF-α
• increase in CD cells
• C-reactive protein (CRP)
• Nitric oxide production
• Antigenic cross reaction
54

55. Conclusion
• Babesia and Plasmodium elicit similar
inflammatory responses during infection
based on their shared antigenic characters.
• Co-infection between the two has been shown
to induce cross-protection
• This concept, if well extrapolated, can be used
in the control of malaria infection
55

56. Some cited references
• Angulo I and Frenso M. (2002). Cytokines in the
pathogenesis of and protection against malaria. Clinical
and Diagnostic Laboratory Immunology. 10: 1145-1152
• Bate CAW, Taverene J and Playfair HL. (1988). Malarial
parasites induced TNF production by macrophages.
Immunology. 64 : 227-231
• Clark IA, Cox FE and Allison AC. (1977). Protection of
mice against Babesia spp. and Plasmodium spp. with
killed Corynebacterium parvum. Parasitology. 74: 9-18
• Dinarello CA. (2000). Proinflammatory cytokines.
Chest. 118 : 503-508
• vanDuivenvoorde LM, Voorberg-van der Wel A, van der
Werff NM, Braskamp G, Remarque EJ, Kondova I,
Kocken CHM, andThomasAW.(2010). Suppression of
Plasmodium cynomolgi in Rhesus Macaques by
coinfection with Babesia microti. Infection and
Immunity. 78:1032-1039
56

57. 57
SEMINAR III
The pathophysiology of malaria and
babesiosis, diagnosis, control and
treatment

58. OUTLINE OF PRESENTATION
• Introduction
• life cycle of Plasmodium and Babesia
• The pathophysiology of malaria and
babesiosis
• Genetic resistance and susceptibility
• Diagnosis, Treatment, interventions and
control programme
• Conclusion
•
58

59. INTRODUCTION
• In the tropics, overlapping symptoms of fever
caused by various types of infectious agents is
commonplace
• Makes malaria culpable in every case of fever
with high index of suspicion drawn from various
human perceptions and thoughts (Ezeoke et al.,
2012)
• Has resulted in a default and conjecture in
prognosis and treatment of malaria (Agomo et
al., 2006)
• Self-administration of drugs to cure ‘’malaria
fever’’ is very common (Das et al., 2013)
59

60. AIMS AND OBJECTIVE OF THE REVIEW
The review will address:
(A) The pathophysiology of malaria and
babesiosis
(B) Genetic resistance and susceptibility to
infection
(C) Diagnosis, Treatment, interventions and
control of the diseases
60

61. The pathophysiology of malaria and babesiosis
• The pathophysiology has been linked to the
expression of diverse antigens by the parasite
• Modification of IRBCs in which they reside
(Schetters and Eling 1999)
• Makes IRBCs stick to RBCs, walls of tiny blood
vessels, major organs e.g. kidneys, lungs, heart
and brain
• “sequestration”,
»results in reduced blood flow to these organs,
causing the severe clinical symptoms
61

62. Possible mechanisms of Pathophysiology
• Grouped into 4 main thematic:
• Mechanical (impaired micro vascular circulation
that include sequestration, rosetting,
aggregation, reduced red cell deformability and
red cell destruction)
• Immunological (host pro-inflammatory response
to Plasmodium antigens and other mediators of
malaria severity)
• Biochemical and electrolyte changes (metabolic
acidosis)
• Neurological changes (CM /CB)
• →→Among these factors, sequestration is critical
to pathological features of the diseases
(Chotivanich et al., 2003).
62

63. Molecules on IRBCs and pathogenicity
• The role of PfEMP1 and VESA (Babesia IRBCs)
• One unique feature of Pf malaria is the appearance of
VSAs on IRBC surface, produced by the parasite and
exported to the surface of IRBCs (Beeson et al., 2008)
• These result in increased rigidity and adhesiveness of
IRBCs to host endothelium and other cell types (Maier
et al., 2008)
• These antigens include: PfEMP1, Riffin (repetitive
interspersed family), Pf60, Stevor (subtelomeric
variable open reading frame )
• Also, knobs (knob associated histidine-rich protein-
KAHRP) on IRBCs (Beeson and Brown 2002)
63

64. Knobs on IRBCs mediates adherence
• Assembly of knobs (knob associated histidine-rich protein-KAHRP) on host
IRBCs that function as physical platforms to anchor the adhesin ( Maier et
al., 2008).
64

65. Infected RBCs wears a boxing glove?
65
Cytoadherence viz:
Endothelial cells, Platelets
dendritic cells Placenta
Rosetting: IE to non IE
Autoagglutination:
IE to IE
→→→Neurological changes
→→→ Mechanical destruction
of RBC
→→→ Metabolic acidosis
Respiratory distress)
→→→Strong Immune
response = Immunopathology
==Anemia, hypoglycemia, CM &CB , Death etc.

66. Receptors and ligands that mediate adhesion
• Receptors on vascular endothelial cells or
placenta to which IRBCs can bind
• These includes: CD36, ICAM1, VCAM1, E-selectin,
PECAM1 (CD31), intergrin, chondroitin sulphate A
(CSA) and hyaluronic acid (Cooke et al., 2005)
• CSA and HA in gestational malaria, CD36 in the
periphery, ICAM-1 and or CD36 in cerebral
malaria (Cooke et al., 1992).
• CD 36 and chondroitin sulfate A are major
endothelial receptors for cytoadherence in terms
of frequency and avidity (Smith and Craig 2005)
66

67. Host cell receptors on Babesia-IE
• Information is sketchy
• However, one of the best studied species with
receptors for adherence is B. bovis
• Thrombospondin, CD36, laminin, and heparin
(O’Connor et al., 1999)
67

68. Adhesion kinetics of IRBCs
• Hallmark of pathogenicity, infectivity and complication
• Viz: binding of IRBC to IRBC, IRBC to non-IRBC, IRBC to
other cells e.g. vascular endothelial cells, platelets,
dendritic cells and syncytiotrophoblasts of the placenta
(Cooke et al., 2005)
• Three thematic from adherence features:
-Cytoadherence: adhesion to endothelial cells,
platelets, dendritic cells and syncytiotrophoblasts of
the placenta
-Rosetting: adhesion to uninfected cells
-Autoagglutination: adhesion to other infected red
blood cells
▪ In babesiosis, cytoadherence have been proven but
rosetting and autoagglutination, none
68

69. Resistance and susceptibility
• In endemic areas asymptomatic carriers of
parasitemia are commonplace (Luzzatto et al
1986).
• Due to acquired immunity(Kitua, 1996)
• Other notions of protections hypothesis :
G6PD deficiency, -ve Duffy blood group
antigens, Sickle hemoglobin genotypes (AS,
SS, AC & SC) Thalassemias, Pyruvate kinase
deficiency etc.
• For babesiosis, none.
69

70. Various intervention & Control methods
Through:
• Case management of malaria (CMM)
• Home-based management of malaria (HMM)
• Use of traditional herbal medicines (THM)
• Vaccine
• Biological and vector control
• Community engagement
• Environmental management (EM)
• Key target: Environment, vector and man [BCC]
Effective management of malaria is prompt and
accurate diagnosis (Murray et al., 2008
70

71. Treatment
• In Nigeria, ACTs are recommended for the
treatment of uncomplicated malaria
• In complicated malaria, hospital management
is often required
71

72. 72
Treatment Regimen for uncomplicated malaria
Source: National malaria strategic plan, 2014-2020
Artemether (20mg)+ Lumefantrine (120mg)
AL
Artesunate (50mg)+ Amodiaquine (153mg)
Age Weight
(kg)
Artemether +
Lumefantrine
AGE/WT (Kg) FIRST
DAY
2ND
DAY
3RD DAY
6month-
3years
5-14 kg 1 tablet twice daily x 3
days
1-6yrs(10-20 kg) 1 tablet
1tablet
1 tablet
1tablet
1 tablet
1tablet
4-8years 15-24 kg 2 tablet twice daily x 3
days
7-12yrs (21-40 kg) 2 tablet
2 tablet
2 tablet
2 tablet
2 tablet
2 tablet
9-14 years 25-34 kg 3 tablet twice daily x 3
days
13+yrs/ (>40kg) 4 tablet
4tablet
4 tablet
4 tablet
4 tablet
4 tablet
>14years >35 kg 1 tablet twice daily x 3
days

73. Treatment of babesiosis
• In humans, most cases of infections are mild and
usually resolve without treatment
• In severe cases, clindamycin and quinine is a drug of
choice (Vannier and Krause, 2012)
• In mild cases, atovaquone/azithromycin combination
has been shown to be effective against B. microti
(Krause et al., 2000).
• Various other pharmacologic interventions have been
tried including chloroquine, tetracycline, primaquine,
sulfadiazine and pyrimethamine, with variable result.
• In hemolytic cases, blood transfusion becomes
inevitable
• In veterinary babesiosis, the use of attenuated vaccines
is a continuing necessity (Shkap et al., 2007).
73

74. 74
Treatment Dose Frequency
Atovaquone
Azithromycin
Adult: 750 mg
Child: 20 mg/kg
(maximum 750 mg/dose)
Every 12 hours
Every 12 hours
Adult: 500 to 1000 mg
250 to 1000 mg
Child: 10 mg/kg
(maximum 500 mg/dose)
5mg/kg
(maximum 250 mg/dose)
On day 1
On subsequent days
On day 1
On subsequent days
Clindamycin and quinine
Adult: 600 mg
Child: 7–10 mg/kg
(maximum 600 mg/dose)
Every 8 hours
Every 6–8 hours
Clindamycin
Intravenous administration
Adult: 300–600 mg
Child: 7–10 mg/kg
(maximum 600 mg/dose)
Every 6 hours
Every 6–8 hours
Quinine Adult: 650 mg
Child: 8mg/kg
Every 6–8 hours
Every 8 hours
Table 2. Treatment regimen of babesiosis Source: Vannier and Krause, 2012.

75. Conclusion
• The clinical manifestation of malaria and
babesiosis involve host tissues and organs
• However the kinetics and components that
result in pathogenicity remain to be fully
understood
• Few of such linkages such as host cell
receptors and parasite ligands have been
identified
• The task in basic research remains to bring to
fore, a potent modality that will ensure
immunity against both diseases
75

76. Suggestions & Recommendations
• Analyze current efforts to solve malaria
problems
• Identify and characterize available resources
and capabilities
• Design and prioritize interventions based on
the epidemiologic situation
• Design a training program for decision makers,
managers, technical staff and CHEWs to
sustain the interventions
• Above all synergy between the community
and policy makers
76

77. Some cited references
• Agomo P.U, Enya V.N, Egbuna K.N, Akindele S.K, Agomo CO,
Okoh HI, Ainna OO, Olukosi YA, Afolabi AS, Akinyele MO,
Iwalokun BA and Okechukwu AN.(2006). Evaluation of Rapid
diagnostic kit in Assessment of Efficacy of Artesunate –
Mefloquine combination. Jour Mal Africa Trop. 2:47-54
• Beeson JG and Brown GV. (2002). Pathogenesis of P
falciparum malaria: the roles of parasite adhesion and
antigenic variation. Cell and Mole Life Sci. 59: 258-271
• COX FEG. (1978). Heterologous immunity between piroplasms
and malaria parasites: the simultaneous elimination of P.
vinckei and B. microti from the blood of doubly infected mice.
Parasitology. 76: 55-60 55
• Oyibo WA, Orok AB, Agomo CO and Iboma G. (2009).
Empirical study of the prevalence of Glucose-6-phosphate
Dehydrogenase (G6PD) enzyme deficiency and protection
against Plasmodium falciparum malaria in Lagos state.
Nigerian Hospital Practice. 3: 84-89
77

78. Review Papers for publications
• Babesia with Plasmodium Coinfection: What if
the host is benefitting?...Submitted
• The recurrent decimal in malaria interventions
and control programmes in sub-Saharan
Africa..Submitted
• The Pattern, Dynamics and nature of
Coinfection
• Babesia and Plasmodium, Any Similarities and
Differences?
78

79. Acknowledgements
• Late Prof A. F. Beyioku
• Prof David Ross-University of Pennsylvania
79

80. 80