STUDIES ON THE PATHOGENESIS OF FEVER WITH INFLUENZAL VIRUSES

A substance with pyrogenic properties appears in the blood streams of rabbits made febrile by the intravenous inoculation of the PR8 strain of influenza A and Newcastle disease viruses (NDV). By means of a technique involving passive transfer of sera from animals given virus to recipient rabbits, the titer of circulating pyrogen was found to be closely correlated with the course of fever produced by virus. Certain properties of the pyrogen are described which differentiate it from the originally injected virus and suggest that the induced pyrogen is of endogenous origin. These properties resemble those of endogenous pyrogens occurring in other forms of experimental fever. The source of virus-induced pyrogen is unknown. In vitro incubation of virus with various constituents of the circulation did not result in the appearance of endogenous pyrogen. Granulocytopenia induced by HN2 failed to influence either fever or the production of endogenous pyrogen in rabbits injected with NDV. Similarly, the intraperitoneal inoculation of NDV into prepared exudates did not modify the febrile response. These findings do not lend support to the possibility that the polymorphonuclear leukocyte is a significant source of endogenous pyrogen in virus-induced fever. It is concluded that the liberation of an endogenous pyrogen from some as yet undefined source is an essential step in the pathogenesis of fever caused by the influenza group of viruses.

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STUDIES ON THE PATHOGENESIS OF FEVER WITH INFLUENZAL VIRUSES

Journal of Experimental Medicine ◽

10.1084/jem.107.3.403 ◽

1958 ◽

Vol 107 (3) ◽

pp. 403-414 ◽

Cited By ~ 20

Author(s):

Elisha Atkins ◽

Wei Cheng Huang

Keyword(s):

Newcastle Disease Virus ◽

Disease Virus ◽

Newcastle Disease ◽

Passive Transfer ◽

Endogenous Pyrogen ◽

Direct Stimulation ◽

Bacterial Endotoxins ◽

Significant Change ◽

Intravenous Inoculation ◽

Stimulation Of

Observations have been made on the fever-inducing properties of an endogenous pyrogen found in the circulation of rabbits after the intravenous inoculation of Newcastle disease virus (NDV). When endogenous pyrogen was given to a normal recipient, a biphasic fever was produced which simulated that seen with bacterial endotoxins. With the use of a technique of serial passive transfer, it has been shown that the "double-humped" response results from two separate actions of the injected pyrogen. The first of these appears to be a direct stimulation of the thermoregulatory centers. The second involves the release of further endogenous pyrogen in the normal recipient to cause, in turn, the second fever peak. Since the injection of endogenous pyrogen did not produce a significant change in the number of circulating leukocytes, it is inferred that this substance is different from either bacterial or tissue polysaccharides. In rabbits rendered tolerant by a previous injection of virus the second fever peak failed to appear and the response to endogenous pyrogen was monophasic. Evidence indicates that the absence of a second fever peak in the tolerant recipient was not due to rise in temperature on the preceding day of virus injection or to the development of either serum inhibitors or tolerance to virus itself. It is postulated that prior mobilization of endogenous pyrogen by virus may have modified the ability of the tolerant recipient to liberate further amounts of this substance in response to an injection of endogenous pyrogen.

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STUDIES ON TUBERCULIN FEVER

Journal of Experimental Medicine ◽

10.1084/jem.131.3.483 ◽

1970 ◽

Vol 131 (3) ◽

pp. 483-498 ◽

Cited By ~ 6

Author(s):

William J. Hall ◽

Lorraine Francis ◽

Elisha Atkins

Keyword(s):

Mononuclear Cells ◽

Reticuloendothelial System ◽

Passive Transfer ◽

Host Cells ◽

Endogenous Pyrogen ◽

Phagocytic Cells ◽

Lymph Node Cells ◽

Intermediate Substance

Utilizing techniques of passive transfer, we have investigated the factors responsible for production of fever when tuberculin is given intravenously to specifically sensitized rabbits. The ability to develop a febrile response to tuberculin could be passively transferred to normal recipients with viable mononuclear cells from peritoneal exudates, spleen, or lymph nodes of donor rabbits sensitized with BCG. Sensitivity was usually apparent 48 hr after transfer, maximal at 7 to 14 days, and rapidly declined thereafter. Granulocytes and nonviable, sonicated, mononuclear cells from similarly sensitized donors were unable to transfer this form of reactivity. Passive transfer of reactivity was also effected with plasma and serum, suggesting that the reaction of antibody with antigen contained in tuberculin is one of the initial steps by which the host cells are activated to release the endogenous pyrogen (EP) that mediates this form of hypersensitivity fever. An intravenous infusion of granulocytes, as well as of several types of mononuclear cells from sensitized donors, made most recipients responsive to the pyrogenic effect of old tuberculin (OT) given 2 hr later. Some of these passively transferred cells, such as the granulocyte and alveolar macrophage, may be activated in vivo by OT, as they are in vitro. However, in the case of splenic and lymph node cells that cannot be activated by OT to produce EP in vitro, it seems likely that an intravenous injection of OT causes these transferred, sensitized cells to liberate an intermediate substance that either directly, or in association with antigen, activates the host's normal cells to produce EP. In support of previous suggestions that leukocytes of several types, as well as phagocytic cells of the reticuloendothelial system, serve as potential sources of EP in tuberculin-induced fever, evidence was presented that OT also activates both granulocytes and mononuclear cells from sterile exudates of BCG-sensitized donors to produce EP in vitro.

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THE PRODUCTION OF FEVER BY INFLUENZAL VIRUSES

Journal of Experimental Medicine ◽

10.1084/jem.90.4.321 ◽

1949 ◽

Vol 90 (4) ◽

pp. 321-334 ◽

Cited By ~ 25

Author(s):

Robert R. Wagner ◽

Ivan L. Bennett ◽

Virgil S. LeQuire

Keyword(s):

Influenza A Virus ◽

Low Temperatures ◽

Influenza A ◽

Immune Serum ◽

Influenza B ◽

Chick Embryos ◽

Febrile Response ◽

Virus Particles ◽

Chicken Erythrocytes

The intravenous injection of the PR8 strain of influenza A virus, the Lee strain of influenza B, and the "B" strain of Newcastle disease virus produces fever in rabbits. This phenomenon has been studied in relation to certain in vitro properties of these viruses. Saline suspensions of virus prepared by centrifugation or elution from chicken erythrocytes produced fever. Fluids from which most of the virus particles had been removed were non-pyrogenic. Exposure to temperatures which destroyed the infectivity of the virus for chick embryos did not prevent fever. However, heating sufficient to destroy the hemagglutinin also rendered virus non-pyrogenic. The injection of erythrocytes onto which virus had been adsorbed produced fever. Heated virus adsorbed onto erythrocytes, which failed to elute, produced no elevation of temperature, although heated virus alone was pyrogenic. Neutralization of virus with specific immune serum prevented fever. Antipyrine was capable of abolishing the febrile response to virus. Certain differences between the febrile response in rabbits to the injection of viruses and that following bacterial pyrogens were noted. The period between injection and beginning of temperature rise is longer with virus than with bacterial pyrogens. Relatively low temperatures inactivate the fever-producing capacity of viruses, whereas bacterial pyrogens withstand prolonged autoclaving, and the neutralization of viral fever by specific immune serum contrasts sharply with the failure of antibody to affect the response to bacterial pyrogens. Certain previous observations on the lymphopenia produced in rabbits by the injection of influenzal viruses were confirmed. The capacity of virus preparations to induce fever in rabbits closely parallels their capacity to induce lymphopenia. It was concluded that the fever-producing property of influenzal viruses is closely associated with the capacity to agglutinate erythrocytes.

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Neutrophils Play an Essential Role in Cooperation with Antibody in both Protection against and Recovery from Pulmonary Infection with Influenza Virus in Mice

Journal of Virology ◽

10.1128/jvi.01210-07 ◽

2008 ◽

Vol 82 (6) ◽

pp. 2772-2783 ◽

Cited By ~ 80

Author(s):

Haruo Fujisawa

Keyword(s):

Influenza Virus ◽

Early Phase ◽

Influenza A ◽

Essential Role ◽

Late Phase ◽

Passive Transfer ◽

Plateau Phase ◽

Virus Propagation ◽

Virus Elimination

ABSTRACT The role of polymorphonuclear leukocytes (PMN) in protection in the early phase and recovery in the late phase of influenza A virus infection was investigated by the depletion of PMN in, and passive transfer of anti-influenza virus antiserum to, mice with pulmonary infections. The depletion of PMN in normal mice by treatment with monoclonal antibody RB6-8C5 both increased the mortality rate and pulmonary virus titers from the early to the late phase after infection and delayed virus elimination in the late phase. The passive transfer of the antiserum to normal mice before or after infection abolished pulmonary virus propagation in the early phase, during 3 days, or rapidly decreased high virus titers in the plateau phase, on days 3 to 5, as well as accelerated virus elimination in the late phase, on day 7, after infection, respectively. The passive transfer of the antiserum to PMN-depleted mice could neither prevent the more rapid virus propagation in the early phase, diminish the higher virus titers in the plateau phase, nor accelerate the markedly delayed virus elimination in the late phase after infection in comparison to those for controls. The antibody responses to the virus began to increase on day 7 after infection in normal and PMN-depleted mice. The prevention of virus replication, cytotoxic activity in virus-infected cell cultures, and phagocytosis of the virus in vitro by PMN were all augmented in the presence of the antiserum. These results indicate that PMN play an essential role in virus elimination in both protection against and recovery from infection, in cooperation with the antibody response.

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THE EFFECT OF POLYSACCHARIDES ON THE REACTION BETWEEN ERYTHROCYTES AND VIRUSES, WITH PARTICULAR REFERENCE TO MUMPS VIRUS

Journal of Experimental Medicine ◽

10.1084/jem.87.5.411 ◽

1948 ◽

Vol 87 (5) ◽

pp. 411-424 ◽

Cited By ~ 10

Author(s):

Harold S. Ginsberg ◽

Walther F. Goebel ◽

Frank L. Horsfall

Keyword(s):

Newcastle Disease ◽

Influenza A ◽

Mumps Virus ◽

Influenza B ◽

Inhibiting Activity

Polysaccharides which cause inhibition of the multiplication of mumps virus in the allantoic sac may or may not cause inhibition of hemagglutination by the virus. Moreover, such substances may or may not prevent adsorption of the virus by erythrocytes. The available evidence indicates that polysaccharides active as inhibitors do not block adsorption of mumps virus by cells of the living allantoic membrane. With influenza A, influenza B, and Newcastle disease viruses, as well as with PVM, there also appears to be a lack of correlation between the in vitro and in vivo inhibiting activity of polysaccharides.

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