NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
324
THE INDIAN JOURNAL OF VETERINARY SCIENCE AND ANIMAL HUSBANDRY [VII, IV
Most of the protozoa of higher animals may conveniently be separated into
two groups, those that live in the digestive tract and those that live in the blood
stream. The intestinal protozoa are most easily influenced by modifying the diet
of the host and hence we have devoted a large part of our effort to this phase of
the problem. Blood-inhabiting protozoa may also be influenced by changes in
the diet of the host, since the blood carries the products of digestion to the tissues.
Temperature, humidity, and muscular activity also may alter the condition of the
host sufficiently to bring about visible reactions of the parasites. Drugs and
sera of various sorts have been employed to change the course of infections,
to eliminate parasites from the host or to vary the medium within the intestine
or blood stream, but these agents could not conceivably operate in nature and
our results along these lines are therefore omitted here.
With these few remarks as an introduction, I will now proceed to present
a running account of our studies.
Our attention was first attracted to this subject while studying the intestinal
protozoa of amphibians. Ciliates of the genus Opalina are commonly present
in the intestine of tadpoles of various species of frogs. They persist in the adults
of certain species of frogs but disappear in the green frog when the tadpoles of this
species undergo metamorphosis and do not ordinarily occur in the adult green frog.
Metcalfe suggested that perhaps the change from the vegetable food of the tadpole
to the animal food of the adult might account for the loss of the opalinids. This
explanation is not satisfactory since other species of frogs that retain their
opalinids after metamorphosis also live on animal food as adults. So far as I
know no one has yet explained why the adult green frog differs from other species
of frogs with respect to the opalinid ciliates.
For several reasons the rat is more favourable than the frog for the experi-
mental study of intestinal protozoa. We therefore transferred our attention to
the rat and soon found that it was possible to modify this animal so as to influ-
ence profoundly its protozoan parasites. We noted first that certain rats that had
been used by Dr. E. V. McCollum for dietary studies were free from trichomonad
flagellates which are usually very abundant in the caecum. Inquiry revealed
the fact that these rats had been fed throughout their lives on a diet high in animal
protein. This led to experiments which gave what appeared to be conclusive
results, since trichomonads disappeared from, or became much less numerous
in, rats that were fed on such a diet instead of what we call a normal diet consisting
largely of carbohydrates.
Then it occurred to us that the intestinal protozoa we were supplying our
students for laboratory study came principally from herbivorous animals, and a
review of the literature soon revealed the fact that very few intestinal protozoa
have been recorded from carnivorous animals. The evidence thus seemed quite
PARASITE REACTIONS TO HOST MODIFICATIONS
325
convincing that for some reason a diet high in animal protein brings about a con-
dition in the intestine that is unfavourable for the growth and reproduction of in-
testinal protozoa. This appeared to be true particularly of trichomonad flagel¬
lates which we studied more thoroughly than we did any other type.
The animal proteins that we used in our early experiments were contained
in beefsteak. We next undertook to determine whether other animal proteins
would have a similar effect. Rats were fed on diets containing 60 per cent of pro-
tein. The protein fed to one group of rats was derived from beefsteak, to
a second from beef liver and to a third from casein. The results were quite striking.
After 20 days rats fed only 20 per cent protein contained on the average about
10,000 trichomonads per cubic millimeter of caecal material, whereas rats fed on
the beefsteak diet gave a count of only 1,000, those fed on the beef liver diet con-
tained 28,000, but those fed on the casein diet only 260. It seemed quite evident
from these results that different types of protein brought about conditions within
the intestine of the host sufficiently different to affect drastically the welfare of
the trichomonads.
Just recently we had an opportunity to try out a diet high in vegetable protein.
Groups of infected rats were fed on a normal diet, on a diet high in animal protein
and on a diet high in vegetable protein, respectively. The animal protein diet
contained 70 per cent of casein and the vegetable protein diet contained 77 per
cent of wheat gluten. The average number of trichomonads per cubic millimeter
of caecal contents was 8,270 in rats fed on a normal diet, 200 in rats fed on animal
protein and 1,137 in rats fed on vegetable protein. Apparently the caecal contents
are adversely affected by the vegetable protein but not as unfavourably as by the
animal protein.
Two factors occurred to us that might account for the situation revealed
by these experiments : first, changes in the hydrogen-ion concentration of the
intestinal contents, and second, changes in the relative number of different types
of bacteria. A preliminary examination of control and experimental animals
indicated that no differences in hydrogen-ion concentration were present that
seemed great enough to account for the results noted. Later a more careful
study was made. The hydrogen-ion concentration of the caecal contents
of rats fed on a normal diet was on the average about 6.78, of those fed on a diet
of beefsteak about 6.82, of those fed on a diet of beef liver about 6.42, and
of those fed on a diet of casein about 7.12. Considering the wide range in the
hydrogen-ion concentration of culture media in which trichomonads live suc-
cessfully, it appears probable that this condition played a relatively minor rôle
in the environmental factors responsible for the growth and multiplication of
these flagellates.
Various investigators have demonstrated that profound changes occur in
the bacterial flora of the rat's intestine when its diet is changed from one consisting
326
THE INDIAN JOURNAL OF VETERINARY SCIENCE AND ANIMAL HUSBANDRY [VII, IV
largely of carbohydrates to one high in animal protein. We were of the opinion
from the very beginning that the effects on the trichomonads were due either
to changes in the types of bacteria resulting from the ingestion of large amounts
of protein or to changes in the products of bacterial activity or to both these fac-
tors. An extensive series of experiments seemed to indicate a definite relation
between types of bacteria and numbers of trichomonads. The character of the
results is indicated in the accompanying table. It will be noted that when rats
were fed on either beef or casein the number of trichomonads decreased markedly
in numbers, proteolytic anaerobes increased in numbers, fermentative anaerobes
increased in numbers coli-aerogenes forms exhibited no definite trend and acid¬
urics decreased in number.
20 per cent protein .
Steak, 10 days . .
Steak, 20 days . .
20 per cent protein .
Casein, 10 days . .
Casein, 20 days . .
20 per cent protein .
Liver, 10 days . .
Liver, 20 days . .
Av. no. trich.
10,570
6,820
880
16,850
720
260
10,151
19,800
28,000
Av. no. anaerobes
Proteo.
2.7
27.1
37.0
112.4
136.0
532.0
125.0
112.0
0.4
Ferment
54,000
352,000
361,000
55,000
73,000
73,000
45,000
550,000
2,440,000
Av. no.
Coli-Aerog.
3,047
6,268
8,050
3,552
1,939
1,174
620
507,730
1,350,000
aerobes
Acidurics
537,000
527,000
188,000
1,070,000
113,000
40,000
810,000
425,000
96,000
On a liver diet the trichomonads increased in number, the proteolytic anae-
robes decreased in number, the fermentative anaerobes increased in number
the coli-aerogenes forms increased in number and the acidurics decreased
in number. Since the proteolytic anaerobes were low in number on a
normal diet, increased in number on the steak and casein diets and decreased
in number on the liver diet, the conclusion seemed justified that these bacteria
were responsible for rendering the intestinal contents unfavourable for the
trichomonads. There was a decrease in the number of acidurics but this likewise
occurred when the favourable liver diet was fed to the rats.
The data then available indicated that on any diet the number of trichomonads
varied inversely with the number of proteolytic anaerobes present.
Sometimes a condition that is unfavourable for one species of protozoon
may not have any obvious effect on other species of the same genus. This led
us to test the effects of a high protein diet on the human trichomonad,
T. hominis, in rats. Our discovery that rat trichomonads can easily be
eliminated by carbarsone treatment gave us trichomonad-free rats to work
with. These were infected orally with T. hominis grown in culture. When fed
PARASITE REACTIONS TO HOST MODIFICATIONS
329
collected 100 faecal samples from natives in Guatemala, examined them when fresh
so as to record the different species present and the relative numbers of each
species, and preserved a sufficient quantity of each specimen with which to deter-
mine the starch content. A large amount of time and effort was expended before
we were able to evaluate our results. Unfortunately our data indicate no
correlation whatever between the presence of starch and the number of species
and individual protozoa in the faeces, and I am inclined to believe that it will not
be easy to establish such a correlation. This means that other methods will have
to be devised before we can hope to explain why modifications of the host resulting
from a diet high in carbohydrates favours the growth and multiplication of
certain intestinal protozoa.
Various other methods of changing the intestinal contents of the host have
been tried but not enough work has been done to warrant discussion except perhaps
that of increasing the viscosity of the medium. Various substances were fed to
rats infected with trichomonads ; the most satisfactory were psyllium seed, agar-
agar and gum arabic. The average number of trichomonads per unit in the caecum
of rats fed on a normal diet was 392, whereas the number per unit in rats fed
on psyllium seed was 55, on agar-agar, 285, and on gum arabic, 7. We also
found that the number of balantidia in rats infected with ciliates from a chimpanzee
was also less when a viscus condition was set up within the intestine. In normal
rats there were counted 347 balantidia per centigram whereas in rats fed on agar-
agar the number was 60, on linseed was 92 and on psyllium seed was 34. In no
case were all of the trichomonads or all of the balantidia eliminated but these
protozoa evidently do not grow and multiply as well when the viscosity of the
intestinal contents is increased by changes in the diet.
Intestinal protozoa appear to be able to withstand temperatures below zero
centigrade for considerable periods of time without obvious damage, but succumb
quickly to high temperatures. This has led to various suggestions involving
the use of heat as a method of eliminating these organisms from the host. For
the most part temperatures high enough to destroy endoparasitic protozoa are in-
jurious or fatal to the host, but in some cases the host survives after the death of
the parasites. For example, the intestine of the large Pacific termite, Termopsis
angusticollis, is swarming with four different types of flagellates and cannot di-
gest the wood it uses for food without the aid of these protozoa. By subjecting
these termites to a temperature of 36° C. for 24 hours all of the flagellates are des-
troyed, but the hosts are not harmed. This is a temperature that might occur
in nature and hence experiments of this type fall within the province of this dis-
cussion. The defaunated termites continue to eat wood, but cannot digest it
and therefore die in about 3 weeks in the midst of plenty. If these hosts are re-
infected they are once more able to utilize the wood they eat and live indefinitely
PARASITE REACTIONS TO HOST MODIFICATIONS
331
a period longer than normal; relapses may occur earlier in the course of the infec-
tion and more frequently than normal; and a larger proportion of the birds die
as a result of the infection. When treated with insulin the parasite curve is lower
than normal throughout the course of the infection. So far as I know, no attempt
has been made to modify refractory foreign hosts in this way so that they may
become more susceptible, but it seems to me probable that positive results would
follow experiments of this nature.
Another method of modifying the host that has been used in the study of
malaria is to change the atmospheric humidity and temperature. Malariologists
have found that an increase in these factors favours the breeding of mosquitoes and
the development of sporozoites within the mosquito, and hence is responsible, at
least in part, for epidemics of malaria. We attempted to determine whether such
changes modify the vertebrate host so as to effect the development of the asexual
and sexual stages in the blood. For this purpose we used canary birds infected with
Plasmodium cathemerium. In one experiment 12 birds were inoculated each with
50 milligrams of infected blood from a single host. Six were maintained under
normal conditions in a room where the temperature was about 70° F. and the
relative humidity about 40 per cent. The other 6 were kept in a special room at
a temperature of 90° F. and a relative humidity of about 50 per cent. The course
of the infections in these 12 birds was carefully followed. The data obtained show
that the average number of sexual and asexual parasites was higher in the experi-
mental birds than in the controls and that both types of parasites were present
in larger numbers in the blood for a longer period. Thus the higher temperature
and humidity appeared to modify the host so that the parasites were able to set up
a more severe infection extending over a longer period of time.
A second experiment was performed in which 4 birds were maintained as
controls and 7 birds were subjected to an increase in temperature and relative
humidity as before. The results confirmed those of the first experiment.
In a third experiment the temperature was increased to 100° F. and the re-
lative humidity to about 90 per cent. Four experimental birds and 3 controls
were used. The control birds exhibited normal infections whereas the experi¬
mental birds suffered unusually severe infections which resulted in their death
These experiments add another method of modifying a host, such as is known
to occur in nature, which has a favourable influence on the parasite.
Although we have no experimental data of our own to offer at present, it
may not be out of place to call attention to the important relation between tem-
perature and the development of malaria parasites in mosquitoes. Low tempera-
tures retard the growth and reproduction of the plasmodia in these insects, and
when the temperature reaches a certain degree development ceases entirely.
The three species of Plasmodium that live in man differ in their reactions to
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PARASITE REACTIONS TO HOST MODIFICATIONS
333
SUMMARY
We have attempted to determine some of the factors that are responsible
for host-parasite specificity among protozoa, that is, the infection, in nature of a
certain species of host by certain species of protozoan parasites. Our plan has
been to note the reactions of natural and foreign parasites to modifications in the
host. In every case the modifications were brought about by changes in the en-
vironment of the host that might easily occur in nature.
Only a beginning has been made but already a number of interesting reac-
tions have been revealed. A carbohydrate diet renders the intestinal contents
of certain species of hosts more favourable than normal for some of the intestinal
protozoa natural to these hosts. A high-protein diet is correspondingly unfavour-
able. Of the possible factors that may play a rôle in these results, changes in
the hydrogen-ion concentrations seem of little or no importance; the character
of the bacteria resulting from these two different kinds of diets may be responsible,
or these protozoa may actually require carbohydrate as a food element.
In one case, Balantidium coli has been successfully colonized in a foreign
host, the rat. This appears to be due solely to a change in diet to one containing
a higher percentage of carbohydrates than is normal for this type of host. How-
ever, no cysts are known to have been formed in the normally refractory host
hence transmission to other individuals of the same species probably does not occur.
We cannot, therefore, consider the rat a normal host of this ciliate until we find
some factor that will stimulate the formation of cysts.
The reactions of the bird malaria parasites to the modifications cited are of
such magnitude as to appear quite striking. Increasing the sugar content of the
blood favours the parasite and decreasing it brings about an unfavourable
condition. Increasing the temperature and relative humidity of the host's en-
vironment also brings about modifications favourable to the parasites.
Changing the periods of light and darkness are followed by definite changes
in the course of infections with malaria organisms in canary birds but whether
this is due to light rays, food, the muscular activity of the bird, or to some other
factor is still to be determined.
At least one result of practical application has developed out of these ex-
periments, that is, the use of a high protein diet for the elimination of certain in-
testinal protozoa of man. Patients suffering from digestive disturbances due to
intestinal protozoa are not numerous but those who are so unfortunate as to be
infected welcome with fervor the relief this type of treatment brings to them.
In conclusion, I wish to emphasize the desirability of investigations directed
towards rendering hosts more favourable as habitats for parasitic protozoa by modi-
fications due to known factors. By this procedure valuable data may be obtained
that might not appear when efforts are aimed solely at the elimination of the
organisms.
NEW LIGHT ON THE LIFE-CYCLE OF THE MALARIA
PARASITE
(Reprinted from the ' Leading Articles ' Section of The Lancet, No. 13, Vol. 1,
1937, 764.)
IT has long been a source of interest to the biologist and of chagrin to the
clinician that the malaria parasite, when banished from the blood stream by
quinine, is able somewhere to maintain its existence. That the parasiticidal effect
of quinine has been at the same time so complete and yet so futile is one of the
notable mysteries of clinical medicine. If it is true that the sporozoites injected
by the mosquito complete their life-cycle in the cells of the circulating blood, then
the infection should be scotched by the ingestion of quinine sufficient to main-
tain a lethal concentration in the blood stream. And yet a patient who has
taken a gramme of quinine daily before and during infection by mosquito bites,
and for every day throughout the incubation period, develops an attack of
malaria precisely as if no drug had been given. The life-history of the parasite
in the vertebral host cannot then be as obvious as all that; for, though
SCHAUDINN described the penetration of sporozoites into red blood corpuscles, no
one it seems has succeeded in repeating his observations.
Some years ago Lieutenant-Colonel S. P. JAMES made the suggestion 1 that
the sporozoites, when they are injected by the mosquito, may be carried to re-
ticulo-endothelial cells of the lungs and other organs in which they complete their
asexual cycle of growth and sporulation—a process already observed in the bird
parasite, halteridium. Colonel James has now confirmed this suggestion for a
malaria parasite itself—not in man, but in the domestic fowl. At a laboratory
meeting of the Royal Society of Tropical Medicine and Hygiene on March 18th,
he domonstrated the life-history of the Plasmodium gallinaceum as worked out by
Mr. P. TATE, Ph.D., and himself at the Molteno Institute in Cambridge. Using
this avian strain, brought from Ceylon by Professor BRUMPT of Paris, JAMES and
TATE have witnessed a cycle of development occurring, not in red blood-cells, but
in the reticulo-endothelial cells of the spleen, liver, kidneys, and particularly the
endothelial cells lining the capillaries of the brain. In chickens which had died
of a malarial attack, despite the destruction by quinine of all the parasites in the
peripheral blood, they found the capillaries of the brain blocked with masses of
schizonts, the result being death from paralysis and coma. Those who were able
to study the slides submitted at the laboratory meeting were left in no doubt
that in avian malaria there is a schizogenous cycle of development occurring in
reticulo-endothelial cells. Parallel observations have been made for the blood-
forming cells by two Chicago workers 2 and for the reticulo-endothelial cells by
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