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Abstract
Individuals from malaria-endemic regions often acquire partial immunity after multiple repeated
infections throughout their lives. This partial immunity prevents them from developing severe
complications and they often remain asymptomatic with a persistent, low parasite density in the
blood, and therefore the necessity for treatment is neglected. These patients with chronic,
asymptomatic malaria serve as a reservoir for Plasmodium parasite transmission, becoming a
major obstacle for eradication efforts. The constant exposure to malaria infection may have
benefits in the short term by conferring protection from acute, severe malaria; however, it may
cause substantially more harm in the long term. Rather than the parasite burden itself, the
complications induced by the dysregulated immune responses and the tissue damage done by the
parasites and their products can cause chronic and irreversible suffering. Furthermore, the
complete clearance of parasites in the body may not lead to complete recovery from the disease
as complications can still persist. The fact that there are chronic pathologies caused by malaria
that mostly remain obscure and have the potential to cause a serious burden has recently been
gaining attention. Here, we present and discuss the evidence of unforeseen pathologies and the
risks associated with malaria.
Keywords: Malaria, chronic inflammation, osteoblast and osteoclast, genomic instability, bone
marrow.
© The Japanese Society for Immunology. 2017. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com
Annually there are more than 200 million cases of malaria infection in humans worldwide.
Although the mortality rate has reduced to less than 500 thousand cases (1), millions of malaria
survivors may still be suffering from malaria-related complications. The five species of
Plasmodium parasites that cause malaria in humans are P. falciparum, P. vivax, P.malariae, P.
ovale and P. knowlesi, each with varying virulence and antigenic variation. The Plasmodium
parasites take advantage of the host for survival and have evolved to acquire strategies to escape
from the host immune attack to ensure successive transmission (2).
Plasmodium parasites require the invertebrate mosquito host and the vertebrate host to
complete the complex parasite life cycle. When the parasites in the form of sporozoites are
injected into the skin of the human host during a mosquito blood meal, most of them travel to the
liver. The traversal of the skin by sporozoites and the subsequent infection in the liver do not
cause clinical symptoms, although host immune responses are initiated (3, 4). Most of the
sporozoites differentiate into hepatocytic merozoites, although P. vivax also forms dormant
hypnozoites in the liver that can be activated to cause relapse upon triggering (5). The merozoites
enter the bloodstream upon hepatocyte rupture to infect erythrocytes.
As a strategy for the parasite survival, the parasites cause erythrocyte membrane
modification and digest the host hemoglobin for a nutrient source (6). The heme released from
hemoglobin digestion is quickly biocrystallized by the parasite into hemozoin to avoid heme-
mediated toxicity. The resultant hemozoin is non-toxic to the parasite but exhibits various
immune-modulatory effects on the host (7, 8). The synchronized rupture of mature, infected
erythrocytes (iRBC) in the schizont stage causes rhythmic chills and fever, and subsequent
erythrocytic infection and hemolysis lead to jaundice and anemia.
Malaria infection causes mild to severe symptoms, depending on both parasite and host
factors. Uncomplicated malaria infection is usually accompanied by acute symptoms like
recurrent fever, nausea, headache, diarrhea, body aches, joint pain and fatigue. In severe malaria
cases, the infection can cause respiratory distress, kidney failure, metabolic acidosis, severe
anemia and cerebral malaria (CM). CM is the most severe complication, which leads to coma
and death due to cerebral hemorrhage and edema caused by blood–brain barrier (BBB)
disruption (9, 10).
Survival of malaria patients is the upmost concern in the endemic regions, where the
focus of treatment is put on rescuing the patients from severe malaria to reduce mortality. The
chronic outcome of repeated infections, relapse and untreated chronic, asymptomatic malaria are
often neglected (11). Some symptoms may not prevail immediately after recovery from infection
but the persisting damage caused by malaria may be evident later in life or upon triggering by
other factors (Fig. 1). In this Special-Issue article, we would like to concentrate on the
“unforeseen” complications caused by malaria, rather than the deadly complications.
Neurological sequelae are generally considered as a common consequence of CM that can persist
for years in children after recovery from P. falciparum infection (12). Recent evidence, however,
suggests that CM is not the only cause of neurological impairment as it has also been noticed in
children infected with less-virulent Plasmodium species or with uncomplicated malaria (13–15).
Moreover, the presence of neurological damage in murine malaria models after recovery from a
single Plasmodium infection in the absence of BBB breakage indicates that the persistent
neurological damage could happen without CM and regardless of early anti-malarial treatment
(16, 17). Clearly, there are complex and unforeseen effects of malaria infection on the brain.
The mechanisms of neurological sequelae are not well understood although several
possibilities and causal factors have been postulated (25). Malaria-induced neurological damage
could be a consequence of focal hypoxic or ischemic injury caused by microvascular obstruction
and inflammation in the brain. Temporary cerebral vessel occlusion has been shown to rapidly
induce platelet and fibrin deposition within the cerebral vessel that prolong blood flow
obstruction, leading to activation of microglia with increased inflammatory responses and
oxidative stress that eventually causes myelin degeneration, neuronal synapse loss and cell death
at the site of the occlusion (26, 27). The cell death caused by ischemic injury mainly resembles
autophagy, with increased numbers of dense punctate dots containing microtubule-associated
protein light chain 3 (LC3) detected in the neuron clusters and epithelial cells, with a lower
extent of apoptotic cell death (26). Moreover, small intracerebral hemorrhages were still apparent
in mice that recovered from CM after anti-malarial treatment (28), suggesting that microglia may
continue to be activated to inflict continuous neuronal injury after recovery from CM (29). The
effect of vessel occlusion on neuronal damage was confirmed in CM patients, with a correlation
of axonal and myelin damage with vessel occlusion in the brain (30). Malaria-induced
neurological damage may also involve other factors such as elevated autoantibodies against
neuronal dendrites and increased excitotoxic kynurenine and quinolinic acid in the cerebrospinal
fluid, which have been detected in malaria patients, being especially higher in those with CM
(31, 32).
Although these studies showed pathology in the cochlea and olfactory only during the
acute phase and did not further evaluate whether the defect is reversible upon recovery from
malaria, nevertheless, individuals with chronic, asymptomatic malaria and those who are
repeatedly infected with malaria may have a higher risk of developing gradual hearing
impairment or distorted odor perception. Still there is a lack of biological markers to identify the
individuals at risk of neurological sequelae soon after recovery from malaria. Being aware of the
possible neurological consequences following recovery from malaria can help early diagnosis,
treatment and rehabilitation before the complications worsen.
It is known that constant and long-term exposure to malaria infection is required for antibody-
mediated protection. However, in reality, patients with chronic malaria generally develop
adaptive immune responses that give rise to short-lived and low-affinity antibodies (42). Why
and how this occurs is not completely understood.
Supporting this, malaria patients were recently found to have shortened telomeres
following a single acute infection and this phenomenon was also detected in multiple organs
(liver, lungs, spleen, heart, kidney and brain) in an avian malaria model in which it correlates
with reduced lifespan of the birds (47, 48). The shortening of telomeres may lead to accelerated
cell senescence, aging and organ dysfunction in populations repeatedly exposed to malaria
infections, implying that these unforeseen chronic outcomes are caused by acute malaria
infection.
The relationship between malaria and EBV infection and their roles in eBL development
are still unclear. However, several lines of evidence suggest that malaria is the driving force for
eBL development. Although the genetic pressure exerted by malaria alone is insufficient to
Another piece of evidence supporting the role of malaria in eBL development is the
ability of a crude extract of Plasmodium to suppress EBV lytic-gene expression—possibly via
TLR9 expressed on B cells—thus inhibiting the lysis of EBV-infected cells while maintaining
EBV in the latent state (52), where the cells are highly prone to chromosomal damage and
malignant transformation.
Overall these studies suggest that EBV may take advantage of malaria infection to
exacerbate genetic instability. Chronic malaria infection, repeated infections and other co-
infections in the region might cumulatively contribute to the chronic antigenic stimulation and
immune dysregulation.
Epidemiological and experimental evidence suggests that malaria may be an indirect risk factor
contributing to susceptibility to and complications of other diseases (57). Bacterial infections
such as salmonellosis and tuberculosis, as well as helminth and HIV infections, are fairly
common in malaria-endemic regions. It is surprising not only that anti-malaria intervention
reduces malaria-specific mortality but also that all-cause morbidity and overall mortality decline,
suggesting that malaria exerts pressure on other diseases (58). It is possible that malaria infection
may cause pathological damage to the lymphoid organs such as spleen, leading to alterations in
The acute and chronic phases of malaria infection dynamically regulate the distribution
and responsiveness of innate and adaptive immune cells. The responses to secondary infections
and vaccinations have been suggested to be partly affected by the skewing of the Th1/Th2
balance during the course of infection; thus the timing of the acquisition of the secondary
infection, relative to malaria, may differentially affect the outcome of the secondary disease or
vaccination (61).
In the case of malaria, recent studies have revealed the complexity of the immune
regulation, which involves the dysregulation of cytokine expression and the expansion of
immune-suppressive subsets such as Tr1 (Foxp3– type 1 regulatory T) cells, Tr27 (IL-27-
producing Foxp3– regulatory T) cells, Tfh1 cells and atypical memory B cells (43, 44, 62, 63).
The immune dysregulation during malaria infection has been shown to involve the inhibition of
Th1 cell development but rather promotes the differentiation of Tr1 cells that co-secrete IL-10
and IFN-γ (also known as type 2 interferon) and suppress effector T cell responses and dampen
humoral immunity (62). These responses were found to be mediated by several factors such as
type 1 interferons (IFN-1) produced by plasmacytoid dendritic cells (64), and IL-27 mainly
produced by the newly defined Tr27 cells (63, 65). The high IL-10 production from Tr1 cells may
counteract the IFN-γ activity by inhibiting macrophage cytokine production and anti-
microbicidal activity (Fig. 2).
Besides its effects on macrophages, chronic malaria may also affect neutrophil function
as a reduced neutrophil oxidative burst was observed among Gambian children with
uncomplicated malaria (70). Mature neutrophils are an important anti-Plasmodium component of
the host (71), but the induction of heme oxygenase-1 during malarial hemolysis increases the
mobilization of immature neutrophils from the bone marrow that lack the oxidative burst to kill
the phagocytosed bacteria (72). However, the role of malaria is not solely on hemolytic anemia,
The gut serves as a vulnerable site for bacteria invasion during malaria. Malaria patients
were commonly found to have mucosal edema and congestion accompanied by superficial
bleeding, microthrombosis and gastric atrophy, which cause them to suffer from gastric
symptoms including epigastralgia, nausea and vomiting (76). Plasmodium parasites were found
to sequester in the small capillaries in the intestinal villi in autopsies of children who died of CM
(77). Intestinal malabsorption and increased gastrointestinal permeability were prevalent in
severe malaria cases (78, 79).The enhanced intestinal permeability was demonstrated, in mouse
model of malaria, to be associated with increased recruitment and activation of mast cells in the
ileal villi and crypts, with elevated histamine and hypoargininemia (80). This study further
showed that the disruption of the intestinal barrier increased the translocation of bacteria. The
pathological damage caused by malaria in the gut has recently been shown to cause dysbiosis
that alters the proportions of microbiota in the intestine (81). A severe malaria infection can
breach mucosal immunity and affect the population of microbiota and vice versa (82, 83),
thereby increasing the severity of pathology and risk of other infections (Fig. 2).
Most of the malaria-endemic areas are in lower socio-economy conditions, in which there is a
lack of adequate healthcare, proper hygiene and nutritional practice that increases the morbidity
of infections. The nutritional status could play a role in controlling the disease severity and
overall outcome. For instance, a very recent study showed that a high-fat diet can exert a
protective effect on liver-stage malaria infection (84).
The disease severity and growth retardation in malaria-endemic regions have often been
associated with malnutrition, but recent observations have brought to light the direct contribution
of the malaria burden on physical growth in these regions (85). Although delayed skeletal
maturation and prominent bone porosity were prevalent in these regions, it has been very
difficult to determine whether malaria is the main cause of these bone defects (86, 87). A
convincing study with proper control groups clearly showed that stunting and wasting were
higher in children exposed to malaria compared with those protected from infection in the same
community (88).
Although these studies in human populations have suggested the potential suppressive
effect of malaria on bone and growth development, recent mouse malaria models have confirmed
the direct acute and the chronic effects of malaria infection on bone remodeling (89). This recent
study showed that a single malaria infection can cause chronic bone loss long after recovery
These novel findings unveil one of the hidden pathologies within the bone tissue caused
by malaria infection that raise our awareness of an unforeseen risk of bone pathology in malaria
patients, especially those with chronic asymptomatic infections, repeated infections and relapses.
How long the Plasmodium products remain in the bone marrow to cause tissue insult is,
however, unknown as is whether their presence would affect bone marrow hematopoiesis.
Mesenchymal stromal cells constitute a large proportion in the bone marrow and play
multiple roles in the regulation of bone remodeling, providing a conducive microenvironment in
specific niches for blood-cell production and development, and regulating the retention and
mobilization of bone marrow cells. Malaria infection may affect stromal cell regulation either
directly via recognition of the parasite antigen or its products, or indirectly by cytokine
dysregulation that affects the osteogenic differentiation and expansion of myeloid progenitors in
the bone marrow.
Unlike other infectious diseases, malaria leaves its signature Plasmodium products in the
bone marrow long-term, even after recovery from infection, introducing foreign material into the
bone marrow environment. It has been shown that osteoclasts, osteoblasts and their precursors
directly respond to these Plasmodium products in the absence of on-going active infection (89).
However, it remains to be explored how the other bone marrow cells interact and respond to
Conclusions
The pathology of malaria is more complex than we thought. Recent studies have revealed that
there are still risks of unknown, unforeseen consequences of malaria that could link to various
complications and diseases. The chronic, hidden complications might be among the obstacles for
socio-economic development while hindering the malaria patients from living a normal, healthy
life and to unleash their full potential for the development of their country (93). An overall health
improvement may also decrease overall morbidity and mortality caused by other opportunistic
diseases. Although treatments mainly focus on major complications, the possibility of chronic
complications should be taken into consideration with follow-up examinations and adjunct
therapies. Understanding the hidden cost of malaria can help to identify the early symptoms
before the development of later complications and to determine the most suitable treatment for
the disease.
Acknowledgements
These studies are supported by Grants-in-Aid for Scientific Research (KAKENHI KIBAN B
grant no. 16H05181) and the Japan Agency for Medical Research and Development (AMED J-
PRIDE 17fm0208021h0001).
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Figure legends
Fig. 1. The unforeseen potential of malaria to cause various chronic complications. Malaria
may induce reversible or permanent damage to the central nervous system that leads to
neurological sequelae. Dysregulation of host immunity during malaria infection may alter
vaccine responses, increase susceptibility to other infections, enhance disruption of uninfected
erythrocytes and increase the tendency of chromosomal damage. Malaria may also cause tissue
pathology within the gastrointestinal tract and the bone.
Fig. 2. Immune dysregulation during malaria infection increases the susceptibility to secondary
infections. Malaria infection inhibits Th1 cell differentiation and expands Tr1 cells via IL-27 from
malaria specific-Tr27 cells and IFN-1 from dendritic cells. Tr1 cells co-express high level of IL-10 and
IFNγ that suppresses the differentiation of the CXCR3- Tfh cells which act as efficient B cell helper,
while inducing the differentiation of the less efficient CXCR3+ Tfh-1 cells. The expansion of Tbet+
atypical B cells mediated by IFNγ has impaired BCR signaling and reduced effector function. The high
IL-10 production during malaria infection also inhibits macrophage responsiveness to IFNγ and
suppresses the microbicidal activity of macrophages to control bacterial growth.
Malaria infection causes dysbiosis in the gut to increase the susceptibility to secondary infection.
Sequestration of iRBC causes capillary breakage in the villi that drives the infiltration and activation of
lymphocytes, neutrophils and mast cells to induce inflammation and disrupt the epithelial tight junctions.
Fig. 3. Hidden pathology of malaria within the bone. The long-term retention of Plasmodium products
in the bone marrow changes the environment in the bone marrow. These Plasmodium products may
interact directly with other bone marrow cells such as mesenchymal stromal cells and hematopoietic stem
cells, or indirectly through cytokines to cause the alteration of bone marrow cellular composition and
function. The accumulation of Plasmodium products in the bone marrow induces inflammation in
osteoclast precursors, osteoblast precursors and mature osteoblasts. The inflammatory cytokines induce
RANKL expression on mature osteoblasts to trigger activation of osteoclast formation which lead to and
increased resorption activity and the bone loss.
Increased
susceptibility to
Gastrointestinal other infections
damage
Y Y
IFN-1
iRBC
CD4+ sequestration
T cell
IFNγ ↓
IL-10↑ vascular disruption
Germinal center ↓
Antibodies ↓ BCR signaling ↓
Antibody ↓
Impaired B
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Bone marrow
Osteoblast
precursor
Osteoclast
Plasmodium
precursor
products
IL-1, IL-6, TNFα
HSC
Osteoblast
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Bone