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The reaction of the African grivet monkey (Cercopithecus aethiops centralis) to yellow fever virus
339 TRANSACTIONS OF TIIE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE.
Vol. XXXVI. No. 6.
.May, 1943.
COMMUNICATIONS.
THE REACTION
0I" T H E A F R I C A N G R I V E T M O N K E Y
(CERCOPITHECUS AETIIIOPS CENTRALIS) TO Y E L L O W FEVER VIRUS. BY
T. P. ItUGItES,
From the Yellow Fever Research Institute, Entebbe, Uganda.*
It is axiomatic in yellow fever epidemiology that epidemics, or epizootics, must result when infected haematophagous insects of a species capable of transmitting this infection by bite are present in adequate numbers among a susceptible population. To the present time some twenty species of mosquitoes have been proven capable of transmitting yellow fever virus by bite ; of these twenty species some ten occur commonly in Eastern Africa, including several species which live in close contact with the human population. In the recent epidemic of yellow fever in western Uganda the infection was, presumably, transmitted to man by Aides (Stegomyia) simpsoni Theobald (MAHAFFY, SMITHBURN, JACOBSand GILLETT, 1942). In the Sudan epidemic of 1940 it is probable that Aides (Stegomyia) metallicus Edwards and Aides (Diceromyia) taylori Edwards were among the more important vectors (LEwis). It is probable that any of these twenty species of mosquitoes would be capable of transmitting yellow fever virus in an epidemic form if infection was introduced from an outside source into a mosquito-infested and non-immune community. * This Institute is supported jointly by the Medical Department of the Government of the Uganda Protectorate and the International Health Division of the Rockefeller Foundation.
340
GRIVET MONKEY AND YELLOW FEVER.
Infection may be introduced into such a community from its hypothetical forest reservoir by any of three alternatives, singly br in combination : (1) by the entry of an infectious human; (2) by the entry of an infected insect; or (3) by the entry of an "infectious animal. It is with one aspect of the last alternative that this investigation is cohcerned. One of the most nearly ubiquitous animals in the East African zone of yellow fever endemicity is the grivet monkey, Cercopithecus aethiops centralis Neuman. This species, or monkeys of closely related subspecies (all belonging to the species Cercopithecus aethiops Linnaeus), occurs commonly in Uganda, in the Belgian Congo, in the Anglo-Egyptian Sudan, and in the remaining parts of the Ethiopian region. These monkeys are migratory and travel in small troops. Although primarily arboreal, they are oftcn observed feeding or travelling on the ground. In many areas they cause annoyance and economic loss through their propensity to raid banana plantations, maize farms and vegetable gardens in search of food. If these animals were capable of circulating yellow fever virus in a concentration adequate to permit the infection of biting insects, a troop of grivet s might distribute infection throughout its range of migration. That infection of this species does occur in nature has been established by observations made by FXNDLAY (1941) in Uganda and in the Sudan and, independently, by workers in this laboratory, that about 20 per cent. of these animals captured in each of two areas of yellow fever endemicity possesscd yellow fever antibodies. EXPERIMENTAL.
This investigation of the susceptibility of Cercopithecusaethiops centralis to yellow fever infection may be divided, conveniently, into three sections : (1) the reaction to pantropic virus administered " artificially" by injection ; (2) the reaction to pantropic virus administered " naturally" by the bite of infected mosquitoes ; and (3) the reaction to neurotropic virus. In each case the plan of investigation was similar. The virus was administered, the animals were bled, Usually daily, thereafter, and the sera so obtained were tested for yellow fever virus content by the intracerebral injection of mice with serial dilutions of the sera. Endpoints were calculated by t h e method of REED and MUENCH (1938). It is unfortunate that monkeys of this species, when captured as adults, do very badly in captivity. Many animals died before being inoculated or shortly thereafter from nonspecific causes. Sections were prepared from the livers of all animals dying after inoculation, but of all tile animals tested, only one, Monkey 22, showed lesions in the liver similar to those observed in rhesus monkeys dying of experimental yellow fever infection.* # \ ¥ c are indebtcd to Dr. K. C. SMITHBURN, of this Institute, for making the pathological examination of this material.
T. P. IIUGItES.
341
The temperature of all inoculated animals was taken twice daily but was so irregular as to be useless as a means of diagnosing infection. In general, fever seemed to accompany the presence of virus in the circulation but numerous nonspecific fevers also occurred. REACTION TO PANTROPIC VIRUS ADMINISTERED BY I N J E C T I O N .
Ten monkeys were inoculated intraperitoneally with 1 ml. of Asibi serum virus in varying dilution and one with 0.5 ml. of rehydrated Asibi virus as shown in Table I. 'I~ABI.E I . CIRCULATION
Cercopithec',}s acthiops centralis.
OF Y E L L O W FEVI'iR V/P, US I N
Day Following Injection Monkey
5 6 7
0 0
8
0 0 0
9
10 11 12 13 14 15
I noculum
I
oi
2
3
0 0 0 0 0 0 0 -t-k
.: _'_ +! +.:+ 0 o 0 -l--!+ Dc~id -:- D e a d i o Io 0 0 0 0 0 0 0 : 0 0 0 0 0 0 .+ , + .... i+ --'+
-t- i "-kl+
i
4
5
2_
"i"
6
7
•-:.
0
-k
Dead
8
~9
HI
i
0 0 0 Dead :
0 0 0
0 0 0
0
Dead 0 0
8
9
I ml. u n d i l u t e d A s i bi ml. Asibi l 0 i ml. A s i bi i 01 ml. A s i bi L0-~ 1 ml. A s i b i 10 -e I ml. A s i bi 10 -2 0.5 ml. r e h y d r a t c d A s i b i 1 ml. A s i bi 10 -2 I ml. A s i bi l 0 -* 1 ml. A s i b i 10 -t : I ml. A s l bi 10 -x
l
D a y F o l l o w i n g M o s q u i t o Bite. Monkey 1
2
3
4
o I o
--
-, + -k 0 + +
I 5
6
7
-t-t--i-
0 +
0 -!-k
0
0 0 0 -i0 -
i
-I0:
M o s q u i t o Species
I
16 17 18 19 20 21 22
I
o
-
0
+
2_
0 0
+ 0
0
0 +
7
i 0 ! 0 0 0~0 0 0 : 0 + 0 0 0 0 0 Dead
Agdes ( S t e g o m y i a ) metallicus Ao'des ( S t e g o m y i a ) a e g y p t i . . . . . . . . . . . . . . . . . . . . . . ,, ,, ,,
Circulating virus was demonstrated in the serum of eight out of the eleven animals inoculated. Of the three which showed no virus in the circulation, Monkeys 9 and 10 received the same virus suspension. This suspension was tested by inoculation into mice at the time when the monkeys were injected
342
GRIVET MONKEY AND YELLOW FEVER.
and it was found to be fully active. Serum taken from each of these two monkeys 21 days after inoculation contained no protective antibodies. The third animal, Monkey 11, received an injection of a rehydrated desiccated virus, a portion of which was injected at the same time into a rhesus monkey. The latter animal succumbed to yellow fever infection. No explanation is available for the failure of these three animals to circulate virus. Prior to inoculation they were bled, as were all animals used in this investigation, and their sera, when examined in the mouse protection test, were shown to be nonprotective. Sera from Monkeys 5, 6, 7 and 8 were tested only for the presence of virus. The results obtained from daily titrations of circulating virus in the four remaining monkeys are shown in Table II. TABLE II. TITRE OF CIRCULATING VIRUS FOLLOgrING ADMINISTRATION BY" INJECTION.
Lethal Doses for Mice per ml. Serum. Day after Injection 1
2 3
4 5 6 7 8 9
10
Monkey 12
Monkey 13
Monkey 14
Monkey 15
0 141 590,700 >3,300,000 >3,300,000 >3,300,000 1,042,800 Dead
0 1,544 1,042,800 >3,300,000 ~3,300,000 23,265 1,042 56 Dcad
0 66 18,876 6,699,000 104 85 0 0 0 0
0 148 10,428,000 8,349 96 Dead
'
:i
It is apparent from these results that, once the infection is established, virus circulates for about the same length of time and in al~out the same concentration as it does in the serum of man or rhesus monkeys suffering from yellow fever infections. However, the reaction seems to be much more irregular and unpredictable than with the other primates mentioned. REACTION TO PANTROPIC VIRUS ADMINISTERED BY MOSQUITO BITE.
Seven additional monkeys were subjected to bites by infected mosquitoes. These insects had been infected by feeding on a rhesus monkey during its first febrile period following injection with Asibi virus. Monkey 16 was bitten by four insects of the species A~des (Stegomyia) metallicus, the remainder were bitten by infected A~des (Stegomyia) aegypti Linnaeus.
T. P. HUGHES.
343
The results obtained from the titrations of circulating virus are shown in Table III. TABLE III. TITRE OF CIRCULATING VIRUS FOLLOWING BITE OF INFECTED .MOSQUITOES.
Day after Biting
1
2 3
4 5 6
7 8
9 10
Lethal Doses ~ r M i e e per ml. Serum. Monkey 16 0 0 10,428 23,100 104,280
Monkey 17
0 7,788 1,042,800 7,854 0 0 0 0 0
Monkey 18
Monkey 19
Monkey 20.
0 1,650 1,042,800 1,207,800 115
0 247 183,I50 33
0 0 0 0
683,100
0
33
33
0
1,471 1,666 216 0 0
0 0 0 0 0
o[ 0 0 0
o , '
0 0 0
Monkey 21
Monkey 22
33,000 3,300,000 13,200,000 330,000,000 7,788,000 Dead
Although there is again a marked lack of uniformity of response, each of the seven monkeys showed virus in the circulation at some time and, with the doubtful exception of Monkey 20, in a concentration high enough to infect mosquitoes. It is of interest that Monkey 22, a very young and small specimen, had the highest concentration of virus in the serum and was the only one of the twenty-two animals used which showed, in liver section, pathological lesions similar to those occurring in rhesus monkeys following fatal infections.
REACTION TO NEUROTROPIC VIRUS.
Only one experiment using neurotropic virus, designed to demonstrate the absence of virueidal substances in the serum of this species of monkey, was performed. Each of four monkeys was given an intraperitoneal injection of neurotropic virus. The virus used was in its 619th serial mouse passage. It contained, when undiluted, 144,540,000 lethal doses for mice per millilitre. Each monkey received an injection of 1 ml., the dilution being decreased by one hundredfold for each animal. The monkeys were bled daily. The sera so obtained were tested for the presence of yellow fever virus and also for yellow fever antibodies. The results obtained arc shown in Table IV.
344
GRIVET
MONKEY AND YELI.OW
FEVER.
TABLe IV. REACTION TO NEUROTROPIC VIRUS.
Monkey 1--Injected with 144,540,000 lethal doses for mice. I)ay
Lethal M o a s e Doses per ml. serum
I
Antibody
,, o f~
1
2 3 4 5 7
0 0
?: 5
0
I
0 0
I
Monkey 2--Injected with 1,445,400 lethal doses for mice. Day
i
L e t h a l M o u s e Doses per ml. Serum
]
Antibody
I
478 4,356 10,395 l 947 59
I
2 3 4 5 7.
Monkey 3--Injected with 14,454 lethal doses for mice. Day
L e t h a l M o u s e Doses per ml. s e r u m
~;
I
Antibody
l
o
4~
0
" " ,!~
i
0 0
o
0
i
T
Monkey 4--Injected with 144 lethal doses for mice. Day
L e t h a l M o u s e Doses per ml. serum
L I
0 0 1 221 77.5
I
Antibody
T. V. HUGIII'S.
345
Each of the monkeys showed circulating virus at some time and all had become immune by the 7th day after inoculation. The experiment.shows the absence of normal virucidal substances in the blood of these animals in tw.9 ways, by the negative results of the protection tests done with sera from early blcedings and also by the demonstration that yellow fever virus multiplies and circulates, even when injected in minimal amounts. The test also demonstrates a marked variation in the response of individual animals, since there is no well-defined relationship apparent between the magnitude of the inoculum on the one hand and the length of the incubation period or the quantity of circulating virus on the other hand. This individual variation in susceptibility has been very apparent in all tests in which monkeys of this.species were used. DISCUSSION. The results obtained with respect to the reaction followingthe administration of virus by injection are similar tothose reported by TIIEILERand I-I~:GIi~S (1935), who invcstigated the reactions of the closely rclated West African " green monkey," then referred to as Lasiopyga callitrichus, which under revised terminology becomes Cercopithecus aethiops sabeus (Linnaeus). To date, about thirty species of primates have been tested for yellow fever susceptibility (HINDLE, 1933), ranging from chimpanzees to lemurs. In many species the multiplication of virus has been experimentally observed. All species become immune following the injection of virus, a fact which may be interpreted as indicating that the vires has multiplied and circulated. Tests by GORDON and i-IuGItES (1936) have shown that, at least with rhesus monkeys, no yellow fever immunity results without the multiplication of virus. It appears highly probable that all primates react similarly to the introduction of yellow fever virus in that the virus multiplies and circulates, but species differ greatly in their clinical response to the presence of this virus. The limited number of primates, including man, living in any given area is probably insufficient to permit them to serve as a permanent reservoir of yellow fever infection, in view of the short duration of the period of circulating virus and the fact that the infection produces a lifelong immunity. It is, however, possible that the lower primates may serve as mobile distributors of virus, especially if the illness produced is not severe, by carrying the infection from the forest to an area infested by domesticated mosquitoes. In this manner primates may serve as one link in the chain of circumstances resulting, finally, in human infection. SUMMARY. Certain individufils among the African grivet monkeys, Cercopithecus aethiops centralis Neuman, are capable of circulating yellow fever virus in high
346
GRIVET MONKEYAND YELLOWFEVER.
concentration following its administration either by injection or by the bite of infected mosquitoes. There is, however, a marked variation in susceptibility among individuals of this species. REFERENCES. FINDLAY, G. 3'I. (1941). Trans. R. Soc. trop. IVied. Hyg., 85, 51. GoaDoN, J. E. & HUCHES, T . P . (1936). ft. lmmunol., 30, 221. HINDJ-~, E. (1933). Trop. Dis. Bull., 30, 278. LEWIS, D.J. In preparation. MAHAVVY,A. F., SMxTrmtra~, K. C., JACOBS,H. R., & GILLETT,J. D. (1942). Trans. R. Soc. trop. Med. Hyg., 86, 9. REED, I,. J. & MUENCH, H. (1938). ~tmer. J. Hyg., 27, 493. THEXLER,M., & HUCHES,T . P . (1935). Trans. R. Soc. trop. Med. tlyg., 9.8, 481.
Vol. XXXVI. No. 6.
.May, 1943.
COMMUNICATIONS.
THE REACTION
0I" T H E A F R I C A N G R I V E T M O N K E Y
(CERCOPITHECUS AETIIIOPS CENTRALIS) TO Y E L L O W FEVER VIRUS. BY
T. P. ItUGItES,
From the Yellow Fever Research Institute, Entebbe, Uganda.*
It is axiomatic in yellow fever epidemiology that epidemics, or epizootics, must result when infected haematophagous insects of a species capable of transmitting this infection by bite are present in adequate numbers among a susceptible population. To the present time some twenty species of mosquitoes have been proven capable of transmitting yellow fever virus by bite ; of these twenty species some ten occur commonly in Eastern Africa, including several species which live in close contact with the human population. In the recent epidemic of yellow fever in western Uganda the infection was, presumably, transmitted to man by Aides (Stegomyia) simpsoni Theobald (MAHAFFY, SMITHBURN, JACOBSand GILLETT, 1942). In the Sudan epidemic of 1940 it is probable that Aides (Stegomyia) metallicus Edwards and Aides (Diceromyia) taylori Edwards were among the more important vectors (LEwis). It is probable that any of these twenty species of mosquitoes would be capable of transmitting yellow fever virus in an epidemic form if infection was introduced from an outside source into a mosquito-infested and non-immune community. * This Institute is supported jointly by the Medical Department of the Government of the Uganda Protectorate and the International Health Division of the Rockefeller Foundation.
340
GRIVET MONKEY AND YELLOW FEVER.
Infection may be introduced into such a community from its hypothetical forest reservoir by any of three alternatives, singly br in combination : (1) by the entry of an infectious human; (2) by the entry of an infected insect; or (3) by the entry of an "infectious animal. It is with one aspect of the last alternative that this investigation is cohcerned. One of the most nearly ubiquitous animals in the East African zone of yellow fever endemicity is the grivet monkey, Cercopithecus aethiops centralis Neuman. This species, or monkeys of closely related subspecies (all belonging to the species Cercopithecus aethiops Linnaeus), occurs commonly in Uganda, in the Belgian Congo, in the Anglo-Egyptian Sudan, and in the remaining parts of the Ethiopian region. These monkeys are migratory and travel in small troops. Although primarily arboreal, they are oftcn observed feeding or travelling on the ground. In many areas they cause annoyance and economic loss through their propensity to raid banana plantations, maize farms and vegetable gardens in search of food. If these animals were capable of circulating yellow fever virus in a concentration adequate to permit the infection of biting insects, a troop of grivet s might distribute infection throughout its range of migration. That infection of this species does occur in nature has been established by observations made by FXNDLAY (1941) in Uganda and in the Sudan and, independently, by workers in this laboratory, that about 20 per cent. of these animals captured in each of two areas of yellow fever endemicity possesscd yellow fever antibodies. EXPERIMENTAL.
This investigation of the susceptibility of Cercopithecusaethiops centralis to yellow fever infection may be divided, conveniently, into three sections : (1) the reaction to pantropic virus administered " artificially" by injection ; (2) the reaction to pantropic virus administered " naturally" by the bite of infected mosquitoes ; and (3) the reaction to neurotropic virus. In each case the plan of investigation was similar. The virus was administered, the animals were bled, Usually daily, thereafter, and the sera so obtained were tested for yellow fever virus content by the intracerebral injection of mice with serial dilutions of the sera. Endpoints were calculated by t h e method of REED and MUENCH (1938). It is unfortunate that monkeys of this species, when captured as adults, do very badly in captivity. Many animals died before being inoculated or shortly thereafter from nonspecific causes. Sections were prepared from the livers of all animals dying after inoculation, but of all tile animals tested, only one, Monkey 22, showed lesions in the liver similar to those observed in rhesus monkeys dying of experimental yellow fever infection.* # \ ¥ c are indebtcd to Dr. K. C. SMITHBURN, of this Institute, for making the pathological examination of this material.
T. P. IIUGItES.
341
The temperature of all inoculated animals was taken twice daily but was so irregular as to be useless as a means of diagnosing infection. In general, fever seemed to accompany the presence of virus in the circulation but numerous nonspecific fevers also occurred. REACTION TO PANTROPIC VIRUS ADMINISTERED BY I N J E C T I O N .
Ten monkeys were inoculated intraperitoneally with 1 ml. of Asibi serum virus in varying dilution and one with 0.5 ml. of rehydrated Asibi virus as shown in Table I. 'I~ABI.E I . CIRCULATION
Cercopithec',}s acthiops centralis.
OF Y E L L O W FEVI'iR V/P, US I N
Day Following Injection Monkey
5 6 7
0 0
8
0 0 0
9
10 11 12 13 14 15
I noculum
I
oi
2
3
0 0 0 0 0 0 0 -t-k
.: _'_ +! +.:+ 0 o 0 -l--!+ Dc~id -:- D e a d i o Io 0 0 0 0 0 0 0 : 0 0 0 0 0 0 .+ , + .... i+ --'+
-t- i "-kl+
i
4
5
2_
"i"
6
7
•-:.
0
-k
Dead
8
~9
HI
i
0 0 0 Dead :
0 0 0
0 0 0
0
Dead 0 0
8
9
I ml. u n d i l u t e d A s i bi ml. Asibi l 0 i ml. A s i bi i 01 ml. A s i bi L0-~ 1 ml. A s i b i 10 -e I ml. A s i bi 10 -2 0.5 ml. r e h y d r a t c d A s i b i 1 ml. A s i bi 10 -2 I ml. A s i bi l 0 -* 1 ml. A s i b i 10 -t : I ml. A s l bi 10 -x
l
D a y F o l l o w i n g M o s q u i t o Bite. Monkey 1
2
3
4
o I o
--
-, + -k 0 + +
I 5
6
7
-t-t--i-
0 +
0 -!-k
0
0 0 0 -i0 -
i
-I0:
M o s q u i t o Species
I
16 17 18 19 20 21 22
I
o
-
0
+
2_
0 0
+ 0
0
0 +
7
i 0 ! 0 0 0~0 0 0 : 0 + 0 0 0 0 0 Dead
Agdes ( S t e g o m y i a ) metallicus Ao'des ( S t e g o m y i a ) a e g y p t i . . . . . . . . . . . . . . . . . . . . . . ,, ,, ,,
Circulating virus was demonstrated in the serum of eight out of the eleven animals inoculated. Of the three which showed no virus in the circulation, Monkeys 9 and 10 received the same virus suspension. This suspension was tested by inoculation into mice at the time when the monkeys were injected
342
GRIVET MONKEY AND YELLOW FEVER.
and it was found to be fully active. Serum taken from each of these two monkeys 21 days after inoculation contained no protective antibodies. The third animal, Monkey 11, received an injection of a rehydrated desiccated virus, a portion of which was injected at the same time into a rhesus monkey. The latter animal succumbed to yellow fever infection. No explanation is available for the failure of these three animals to circulate virus. Prior to inoculation they were bled, as were all animals used in this investigation, and their sera, when examined in the mouse protection test, were shown to be nonprotective. Sera from Monkeys 5, 6, 7 and 8 were tested only for the presence of virus. The results obtained from daily titrations of circulating virus in the four remaining monkeys are shown in Table II. TABLE II. TITRE OF CIRCULATING VIRUS FOLLOgrING ADMINISTRATION BY" INJECTION.
Lethal Doses for Mice per ml. Serum. Day after Injection 1
2 3
4 5 6 7 8 9
10
Monkey 12
Monkey 13
Monkey 14
Monkey 15
0 141 590,700 >3,300,000 >3,300,000 >3,300,000 1,042,800 Dead
0 1,544 1,042,800 >3,300,000 ~3,300,000 23,265 1,042 56 Dcad
0 66 18,876 6,699,000 104 85 0 0 0 0
0 148 10,428,000 8,349 96 Dead
'
:i
It is apparent from these results that, once the infection is established, virus circulates for about the same length of time and in al~out the same concentration as it does in the serum of man or rhesus monkeys suffering from yellow fever infections. However, the reaction seems to be much more irregular and unpredictable than with the other primates mentioned. REACTION TO PANTROPIC VIRUS ADMINISTERED BY MOSQUITO BITE.
Seven additional monkeys were subjected to bites by infected mosquitoes. These insects had been infected by feeding on a rhesus monkey during its first febrile period following injection with Asibi virus. Monkey 16 was bitten by four insects of the species A~des (Stegomyia) metallicus, the remainder were bitten by infected A~des (Stegomyia) aegypti Linnaeus.
T. P. HUGHES.
343
The results obtained from the titrations of circulating virus are shown in Table III. TABLE III. TITRE OF CIRCULATING VIRUS FOLLOWING BITE OF INFECTED .MOSQUITOES.
Day after Biting
1
2 3
4 5 6
7 8
9 10
Lethal Doses ~ r M i e e per ml. Serum. Monkey 16 0 0 10,428 23,100 104,280
Monkey 17
0 7,788 1,042,800 7,854 0 0 0 0 0
Monkey 18
Monkey 19
Monkey 20.
0 1,650 1,042,800 1,207,800 115
0 247 183,I50 33
0 0 0 0
683,100
0
33
33
0
1,471 1,666 216 0 0
0 0 0 0 0
o[ 0 0 0
o , '
0 0 0
Monkey 21
Monkey 22
33,000 3,300,000 13,200,000 330,000,000 7,788,000 Dead
Although there is again a marked lack of uniformity of response, each of the seven monkeys showed virus in the circulation at some time and, with the doubtful exception of Monkey 20, in a concentration high enough to infect mosquitoes. It is of interest that Monkey 22, a very young and small specimen, had the highest concentration of virus in the serum and was the only one of the twenty-two animals used which showed, in liver section, pathological lesions similar to those occurring in rhesus monkeys following fatal infections.
REACTION TO NEUROTROPIC VIRUS.
Only one experiment using neurotropic virus, designed to demonstrate the absence of virueidal substances in the serum of this species of monkey, was performed. Each of four monkeys was given an intraperitoneal injection of neurotropic virus. The virus used was in its 619th serial mouse passage. It contained, when undiluted, 144,540,000 lethal doses for mice per millilitre. Each monkey received an injection of 1 ml., the dilution being decreased by one hundredfold for each animal. The monkeys were bled daily. The sera so obtained were tested for the presence of yellow fever virus and also for yellow fever antibodies. The results obtained arc shown in Table IV.
344
GRIVET
MONKEY AND YELI.OW
FEVER.
TABLe IV. REACTION TO NEUROTROPIC VIRUS.
Monkey 1--Injected with 144,540,000 lethal doses for mice. I)ay
Lethal M o a s e Doses per ml. serum
I
Antibody
,, o f~
1
2 3 4 5 7
0 0
?: 5
0
I
0 0
I
Monkey 2--Injected with 1,445,400 lethal doses for mice. Day
i
L e t h a l M o u s e Doses per ml. Serum
]
Antibody
I
478 4,356 10,395 l 947 59
I
2 3 4 5 7.
Monkey 3--Injected with 14,454 lethal doses for mice. Day
L e t h a l M o u s e Doses per ml. s e r u m
~;
I
Antibody
l
o
4~
0
" " ,!~
i
0 0
o
0
i
T
Monkey 4--Injected with 144 lethal doses for mice. Day
L e t h a l M o u s e Doses per ml. serum
L I
0 0 1 221 77.5
I
Antibody
T. V. HUGIII'S.
345
Each of the monkeys showed circulating virus at some time and all had become immune by the 7th day after inoculation. The experiment.shows the absence of normal virucidal substances in the blood of these animals in tw.9 ways, by the negative results of the protection tests done with sera from early blcedings and also by the demonstration that yellow fever virus multiplies and circulates, even when injected in minimal amounts. The test also demonstrates a marked variation in the response of individual animals, since there is no well-defined relationship apparent between the magnitude of the inoculum on the one hand and the length of the incubation period or the quantity of circulating virus on the other hand. This individual variation in susceptibility has been very apparent in all tests in which monkeys of this.species were used. DISCUSSION. The results obtained with respect to the reaction followingthe administration of virus by injection are similar tothose reported by TIIEILERand I-I~:GIi~S (1935), who invcstigated the reactions of the closely rclated West African " green monkey," then referred to as Lasiopyga callitrichus, which under revised terminology becomes Cercopithecus aethiops sabeus (Linnaeus). To date, about thirty species of primates have been tested for yellow fever susceptibility (HINDLE, 1933), ranging from chimpanzees to lemurs. In many species the multiplication of virus has been experimentally observed. All species become immune following the injection of virus, a fact which may be interpreted as indicating that the vires has multiplied and circulated. Tests by GORDON and i-IuGItES (1936) have shown that, at least with rhesus monkeys, no yellow fever immunity results without the multiplication of virus. It appears highly probable that all primates react similarly to the introduction of yellow fever virus in that the virus multiplies and circulates, but species differ greatly in their clinical response to the presence of this virus. The limited number of primates, including man, living in any given area is probably insufficient to permit them to serve as a permanent reservoir of yellow fever infection, in view of the short duration of the period of circulating virus and the fact that the infection produces a lifelong immunity. It is, however, possible that the lower primates may serve as mobile distributors of virus, especially if the illness produced is not severe, by carrying the infection from the forest to an area infested by domesticated mosquitoes. In this manner primates may serve as one link in the chain of circumstances resulting, finally, in human infection. SUMMARY. Certain individufils among the African grivet monkeys, Cercopithecus aethiops centralis Neuman, are capable of circulating yellow fever virus in high
346
GRIVET MONKEYAND YELLOWFEVER.
concentration following its administration either by injection or by the bite of infected mosquitoes. There is, however, a marked variation in susceptibility among individuals of this species. REFERENCES. FINDLAY, G. 3'I. (1941). Trans. R. Soc. trop. IVied. Hyg., 85, 51. GoaDoN, J. E. & HUCHES, T . P . (1936). ft. lmmunol., 30, 221. HINDJ-~, E. (1933). Trop. Dis. Bull., 30, 278. LEWIS, D.J. In preparation. MAHAVVY,A. F., SMxTrmtra~, K. C., JACOBS,H. R., & GILLETT,J. D. (1942). Trans. R. Soc. trop. Med. Hyg., 86, 9. REED, I,. J. & MUENCH, H. (1938). ~tmer. J. Hyg., 27, 493. THEXLER,M., & HUCHES,T . P . (1935). Trans. R. Soc. trop. Med. tlyg., 9.8, 481.