Relapse - Advances in Parasitology - page 140

P. vivax in temperate zones has evolved to adapt to the long winters
across the Northern Hemisphere. The large proportion of sporozoites
dedicated to latency, and the relatively low number of relapses compared
with the tropical strains may reflect the high natural wastage of hypnozo-
ites in hepatocytes, which die before the hypnozoites become activatable.
In experimental P. cynomolgi bastianelli infection in the Rhesus monkey,
Garnham observed a 10-fold reduction in the number of hypnozoites in
serial liver biopsies over a 9-month period, but it is unclear how much of
this reduction resulted from activation and how much was from cell death
( James, 1931b ).
The hypnozoite can be considered as an unactivated sporozoite. If the
duration of pre-erythrocytic development of the liver stage is similar for
sporozoites and hypnozoites, as seems likely, then activation occurs around
the time of presentation with acute malaria illness (of any species). If the
ALH hypothesis is correct, then the key biological difference between fre-
quent-relapse and long-latency P. vivax is in the temporal distribution of
susceptibility to activation among the sporozoites.
Thus, the ALH hypothesis proposes that there is a biological clock, that
is most evident in temperate strains, which determines latency in P. vivax .
This clock, which could be an intrinsic parasite clock or could reflect a
host-parasite interaction, determines the duration of the interval before
the hypnozoite becomes susceptible to activation. Once the hypnozoite
becomes susceptible, there is then a separate sensing mechanism which
determines whether or not activation does occur. The trigger could be
either a positive-activation stimulus or removal of inhibition. This mecha-
nism may activate spontaneously once the hypnozoite has become sus-
ceptible, and spontaneous activation presumably usually explains the first
relapse after a long-latent period, but, once susceptible, activation is much
more likely with an external systemic trigger such as malaria illness. Acti-
vation must involve signalling via the infected hepatocyte (which is very
sensitive to systemic inflammatory responses). Importantly, the individual
probability of activation for each hypnozoite is low, allowing accumula-
tion of latent but 'activatable' hypnozoites after each sporozoite inoculum.
This implies that people living in vivax endemic areas commonly harbour
latent but 'activatable' hypnozoites. In endemic areas of South East Asia, if
patients who acquire falciparum malaria are representative of the popula-
tion, this is approximately one quarter to one-third. The periodicity of
P. vivax relapses is derived from the sequential iterative activation of hyp-
nozoites by illness.