Pyrogenicity of human adenoviruses

Nobuo Kato1

Department of Bacteriology, Nagoya University School of Medicine, Nagoya, Aichi 466-8550, Japan1

Author for correspondence: Nobuo Kato. Present address: Aichi Medical University, Nagakute, Aichi 480-1195, Japan. Fax +81 561 63 4940. e-mail 2015{at}gk.amu.aichi-med-u.ac.jp


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High doses (>1·56x107 p.f.u.) of purified preparations of human adenovirus types 3, 5 and 8 exhibited definite pyrogenic activity when injected intravenously into rabbits. Complete pyrogenic tolerance was obtained not only with homologous types but also with heterologous types of adenovirus. No pyrogenic cross-tolerance was observed between each of these three adenovirus types and paramyxovirus pyrogen or bacterial lipopolysaccharide. Adenovirus pyrogenicity was retained after UV-inactivation, whereas it was inactivated by heating at 56 °C for 30 min. Adenovirus pyrogenicity was not neutralized by mixing with homologous type-specific antiserum but non-pyrogenic doses (107 p.f.u.) of adenovirus types 3, 5 and 8 became highly pyrogenic in the presence of type-specific antibodies at the optimal virus:antibody ratio. This enhanced pyrogenicity depended upon the virus–antibody complex. From these results, it is probable that the pyrogenic activity of the virus–antibody complex, rather than the pyrogenic activity of the virions, is the main contributor to fever in adenovirus infection under actual physiological conditions.


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Fever in viral and bacterial infections in humans is elicited by the action of endogenous pyrogen, produced by phagocytes, in response to infectious agents as exogenous pyrogens. Several known cytokines induce fever in experimental animals and are believed to be candidate endogenous pyrogens. These cytokines include interleukin (IL)-1 (Dinarello, 1992 ), IL-6 (Dinarello et al., 1991 ; Akira & Kishimoto, 1992 ), tumour necrosis factor-{alpha} (TNF-{alpha}) (Vassalli, 1992 ), interferon-{gamma} (Dinarello et al., 1984 ), IL-8 (Zampronio et al., 1994 ) and macrophage inflammatory protein-1{alpha} (Davatelis et al., 1989 ). A number of reports have appeared on the pyrogenic effects of influenza viruses and other myxoviruses and paramyxoviruses since the first paper (Bennett et al., 1949 ). There have been many fewer studies on the pyrogenicity of other viruses. Pyrogenic activities have so far been reported with Western equine encephalitis virus (Fastier, 1952 ), coxsackievirus (King, 1962 , 1964 ) and herpesvirus (Tokumaru, 1967 , 1968 ). It was reported that no pyrogenicity was found with vaccinia virus (King, 1962 ) and also with poliovirus and echo virus (Siegert, 1967 ; Grossgebauer, 1967 ). Subsequently, regarding the pathogenicity of fever in rabbits infected intradermally with vaccinia virus, some evidence was presented suggesting that early humoral antibodies were involved in the induction of fever (Grossgebauer, 1972 ). More recently, it was demonstrated that several vaccinia virus strains, including smallpox vaccines that express soluble IL-1 receptors, which bind IL-1{beta} but not IL-1{alpha}, prevent the febrile response in infected mice, whereas strains that lack the receptor naturally or through genetic engineering induce fever, and that the vaccinia virus-induced fever is inhibited with antibodies to IL-1{beta} (Alcami & Smith, 1996 ). These findings indicate that IL-1{beta}, rather than other cytokines, is the major endogenous pyrogen in poxvirus infection (Alcami & Smith, 1996 ).

Human adenoviruses primarily cause respiratory, gastrointestinal and ocular infections in humans and are divided into six subgroups (A to F) based on several biochemical and antigenic characteristics (Horwitz, 1996 ; Shenk, 1996 ). Respiratory tract adenovirus infection exhibits various clinical forms, including pharyngitis, exudative tonsillitis, pharyngoconjunctival fever and pneumonia (Horwitz, 1996 ). In most of these clinical forms, fever is no doubt one of the dominant clinical symptoms. There have been a number of earlier reports dealing with adenovirus pyrogenicity and these have reported that adenoviruses failed to induce fever in rabbits (King, 1962 ; Siegert, 1967 ; Grossgebauer, 1967 ). In this communication, I have re-examined this phenomenon and show that adenoviruses can exhibit pyrogenicity in rabbits.

Human adenovirus types 3, 5 and 8 were used because they belong to different groups (B, C and D, respectively) and produce distinct disease syndromes in typical cases (Horwitz, 1996 ). Types 5 and 8 were originally isolated from patients and type 3 was the prototype strain (Trim). Adenoviruses were propagated and assayed in HeLa cell cultures. HeLa cells were grown in Eagle’s minimal essential medium (MEM) supplemented with 10% heat-inactivated foetal bovine serum. Eagle’s MEM without serum was used for maintenance of cells after virus inoculation. For large-scale virus production, 10 cultures of HeLa cells in 18 oz. bottles were inoculated with virus, harvested after 5 days of infection, suspended in 30 ml PBS, subjected to five cycles of freezing and thawing and homogenized by the fluorocarbon technique (Valentine & Pereira, 1965 ). The extract of infected HeLa cells was centrifuged at 40000 g for 1 h to sediment virus particles and purified virus was obtained by two cycles of CsCl gradient ultracentrifugation (Norrby, 1969 ). The titres of purified preparations were determined by a plaque assay and found usually to contain 1–3x109 p.f.u./ml. For a control, an extract of uninfected HeLa cells was prepared in the same way and was confirmed to exhibit no detectable pyrogenicity. Parainfluenza virus type 1 (HVJ or Sendai virus) Nagoya 1-60 strain (Kato et al., 1961 ) used as paramyxovirus pyrogen was propagated in the allantoic cavity of embryonated eggs, purified by differential centrifugation (Kato & Hara, 1961 ) and assayed by haemagglutinin (HA) titrations (Kato et al., 1965 ). For preparation of antisera to adenoviruses, rabbits were inoculated intramuscularly with 5 ml extract of infected HeLa cells mixed with Freund’s complete adjuvant. An intravenous booster injection of 2 ml of the extract was given 4 weeks later and the rabbits were exsanguinated after another week. Antiserum to HVJ was produced in rabbits by three intravenous injections (3–4 days apart) of 3 ml UV-inactivated purified vaccine containing 10240 HA units/ml (Kato, 1967 ). Bacterial lipopolysaccharide (LPS)was extracted from Salmonella enteritidis NUB1 strain by the phenol–water method (Westphal & Jann, 1965 ) and further purified (Kato et al., 1976 ).

For the pyrogen test, rabbits weighing 2–3 kg were used. Rectal temperatures were taken by a thermistor thermometer inserted 5 cm into the rectum. Temperature measurements were made at 30 min intervals for 1 h before injection of test material and for 6 h after injection. Material to be tested was injected into the marginal auricular vein of rabbits and elevation in temperature above a baseline temperature was determined. The mean response of three animals was plotted against time. Fever was considered significant if the rectal temperature increased by 0·4 °C above the mean pre-inoculation temperature. The fever index was assessed by determining the area under each temperature curve up to 6 h with a planimeter and was expressed as °Ch (Coates et al., 1986 ). Glassware used in the assay of pyrogen was sterilized by heating in an oven at 160 °C for 2 h. For injections, sterile pyrogen-free disposable syringes and needles were used. Water used for solutions and buffers was first deionized and then made pyrogen-free by distillation in a glass still.

Purified preparations of adenovirus types 3, 5 and 8 were adjusted so as to contain 109 p.f.u./ml virus. One ml aliquots of undiluted suspension and suspensions diluted 1:4, 1:16, 1:64, 1:256 and 1:1024 were injected intravenously into rabbits and febrile responses were assessed. The results with type 3 adenovirus are shown in Fig. 1(a). Injection of undiluted preparations resulted in a sharp elevation in body temperature, which started without a significant lag period and reached a peak 1 h post-injection (p.i.). Thereafter, the fever tended to decline rapidly, but it elevated again slightly later than 2·5 h and produced a second peak, which was much lower than the first peak, 3·5 h p.i. Fever returned to levels <0·4 °C by 6 h p.i. With decreasing doses of purified virus preparations, the peak level of temperature became lower and the length of time to reach the peak temperature was elongated depending upon the dose of virus injected. The highest dilution (the lowest virus dose) retaining significant pyrogenic activity (>0·4 °C) was 1:64 (1·56x107 p.f.u.). Fever patterns and the lowest pyrogenic virus dose with injections of adenovirus types 5 and 8 were very similar to those resulting from injection of type 3, except that the second peak was not detectable after injection of type 5. After UV irradiation capable of inactivating the infectivity completely (Kato, 1967 ), the pyrogenicity of adenovirus types 3, 5 and 8 was retained. Heating at 56 °C for 30 min efficiently inactivated both the infectivity and the pyrogenicity of all three types of adenovirus.



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Fig. 1. Pyrogenicity of a purified preparation of adenovirus type 3 (a) and pyrogenic tolerance to the homologous adenovirus type (b) and to heterologous adenovirus types (c, d). (a) The purified virus preparation was adjusted to 109 p.f.u./ml. Materials to be tested were undiluted ({circ}) or diluted 1:4 ({bullet}), 1:16 ({triangleup}), 1:64 ({blacktriangleup}), 1:256 ({square}) and 1:1024 ({blacksquare}). One ml of each dilution was injected. Mean fever indices for each group were 4·69, 3·96, 2·18, 2·10, 0·95 and 0·45, respectively. (b) Febrile responses to adenovirus type 3 given on the first day ({circ}) and on the second day ({bullet}). Mean fever indices in the first and second response were 4·69 and 1·17. (c) Febrile responses to adenovirus type 3 given on the first day ({circ}) and to adenovirus type 5 given on the second day ({bullet}). Mean fever indices in the first and second response were 5·00 and 0·95. (d) Febrile responses to adenovirus type 3 given on the first day ({circ}) and to adenovirus type 8 given on the second day ({bullet}). Mean fever indices were 4·15 and 1·94. In (b)–(d), 1 ml of undiluted purified virus preparation of each type was injected at each injection.

 
Febrile responses to homologous types of adenovirus injected on the second day were investigated in rabbits that had received each of types 3, 5 or 8 on the first day. With respect to all these types, the febrile response on the second day was much lower than the response on the first day (results with type 3 are shown in Fig. 1b). In further experiments, febrile responses to heterologous types of adenovirus injected on the second day were investigated in rabbits that had received each of types 3, 5 or 8 on the first day. In every combination of these three types of virus, cross-tolerance was observed in reciprocal cross-tests. The results with type 3–type 5 and type 3–type 8 are shown in Fig. 1(c, d). The degrees of cross-tolerance among heterologous types of adenovirus were very similar to those of tolerance to the homologous types.

Cross-tolerance between adenovirus pyrogens and paramyxovirus pyrogen (HVJ) or LPS was studied (Fig. 2). Adenovirus type 8 was used as adenovirus pyrogen. No cross-tolerance was found between adenovirus type 8 and HVJ or LPS. The febrile reaction following intravenous injection of HVJ had a longer lag period of about 1 h, after which monophasic fever ensued, reaching a peak level 3–4·5 h p.i. LPS induced a febrile response without a significant lag period and reached a peak 1·5–2 h p.i. These fever patterns resulting from HVJ and LPS did not differ significantly regardless of whether each pyrogen was administered first or it was administered on the second day after adenovirus type 8 was administered on the first day. Also, the fever pattern caused by adenovirus type 8 was not changed by a prior injection of HVJ or LPS. Experimental results very similar to those with type 8 described here were obtained with adenovirus types 3 and 5.



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Fig. 2. Lack of pyrogenic cross-tolerance between adenovirus type 8 ({circ}) and HVJ ({bullet}) or LPS ({blacktriangleup}). Febrile responses are shown to adenovirus type 8 given on the first day and HVJ given on the second day (a), HVJ given on the first day and adenovirus type 8 given on the second day (b), adenovirus type 8 given on the first day and LPS given on the second day (c) and LPS given on the first day and adenovirus type 8 given on the second day (d). Adenovirus type 8 material for injection was the same as in Fig. 1. The dose of HVJ used for injection was 2560 HA units and the dose of LPS for injection was 1 µg. Respective mean fever indices in the first and second responses were 5·79 and 6·02 (a), 5·88 and 6·43 (b), 5·25 and 6·59 (c) and 6·95 and 6·00 (d).

 
The pyrogenicities of adenovirus types 3, 5 and 8 were not neutralized by addition of homologous antisera. On the contrary, when sub-pyrogenic doses (1 ml of purified virus preparations diluted 1:100; virus titres of 107 p.f.u./ml) of adenovirus types 3, 5 and 8 were mixed with the homologous antisera, their pyrogenicities were enhanced markedly and the enhancing effect of antiserum was strictly type-specific. Antiserum against adenovirus type 3 was diluted and the relationship between dilution of the antiserum and its pyrogenicity-enhancing activity was investigated (Fig. 3a). Judging from the results presented, the mixture of adenovirus type 3 and the homologous antiserum had a pyrogenic effect only within certain limits of virus:antibody ratio. In the case of type 3, the pyrogenicity-enhancing activity was highest when the virus was mixed with the antiserum diluted 1:2. When adenoviruses were mixed with homologous antisera, adenoviruses aggregated. The aggregation of adenovirus occurred most markedly when viruses were mixed with antisera at the optimal virus:antibody ratio for pyrogenicity-enhancing activity. Aggregates of adenovirus type 3 formed by mixing the homologous antiserum at the optimal virus:antibody ratio were collected by low-speed centrifugation, washed twice with PBS and assessed for pyrogenicity, together with the supernatant after removal of the aggregates (Fig. 3b). The pyrogenicity was mostly recovered from the aggregates of virus and antibody but not significantly from the supernatant. For comparison, the effect of the antiserum on the pyrogenicity of HVJ was investigated (Fig. 3c). The results clearly indicated that the pyrogenicity of HVJ was neutralized completely by mixing with the homologous antiserum and that the degree of neutralization was lowered by dilution of the antiserum.



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Fig. 3. Effect of mixing with homologous antiserum on the pyrogenicity of adenovirus type 3 and HVJ. (a) One ml of a purified preparation of adenovirus type 3 diluted 1:100 (107 p.f.u./ml) was mixed with 1 ml undiluted antiserum ({bullet}), antiserum diluted 1:2 ({triangleup}), 1:4 ({blacktriangleup}) or 1:8 ({square}) or PBS ({circ}). The mixtures were incubated at 37 °C for 30 min and then injected. Mean fever indices for each group were 3·44, 6·70, 5·55, 0·87 and 1·46, respectively. (b) One ml of a purified preparation of adenovirus type 3 diluted 1:100 (107 p.f.u./ml) was mixed with 1 ml homologous antiserum diluted 1:2. Virus–antibody complex was separated after incubation at 37 °C for 30 min. Febrile responses to virus–antibody complex ({circ}) and to supernatant after the removal of virus–antibody complex ({bullet}) are shown. Mean fever indices for each group were 5·28 and 1·49. (c) One ml of a purified preparation of HVJ (2560 HA units/ml) was mixed with 1 ml undiluted homologous antiserum ({bullet}), antiserum diluted 1:2 ({triangleup}), 1:4 ({blacktriangleup}) or 1:8 ({square}) or PBS ({circ}). The mixtures were incubated at 37 °C for 30 min and then injected. Mean fever indices were 0·15, 0·49, 0·63, 1·48 and 4·84, respectively.

 
The data presented in this paper demonstrate that virions of adenovirus types 3, 5 and 8 exhibit pyrogenicity when injected intravenously into rabbits. The pattern of fever induced by intravenous injection of a large dose (109 p.f.u.) of adenovirus appears to be distinct from that induced by other viruses and LPS and it resembles the fever pattern produced by endogenous pyrogen (pyrogenic cytokines), which is characterized by a rapid rise of temperature without a significant lag period and a relatively rapid decline of fever (Atkins, 1960 ). However, the properties of adenovirus pyrogenicity are different from those of endogenous pyrogen in that pyrogenic tolerance to a secondary injection of adenovirus can be induced by a prior injection of either homologous or heterologous adenovirus, whereas endogenous pyrogen has been shown to be active on repeated administrations (Atkins, 1960 ). Local release of IL-1{beta}, TNF-{alpha} and IL-6 was observed following airway administration of adenovirus or adenovirus vectors in rats (Ginsberg et al., 1989 ) and mice (Ginsberg et al., 1991 ). Elevated levels of IL-6 were also observed in serum following airway delivery to humans (Crystal et al., 1994 ), rats (Ginsberg et al., 1989 ) and mice (Ginsberg et al., 1991 ). In addition, increased levels of IL-8 were observed in the bronchoalveolar lavage fluid following airway delivery to macaques (Wilmott et al., 1996 ). Recently, it was shown that infection with adenovirus or adenovirus vectors stimulates the Raf/MAPK signalling pathway and induces IL-8 expression in HeLa cells and that IL-8 mRNA accumulation occurs early in the infection process (evident at 20 min p.i.) (Bruder & Kovesdi, 1997 ). Rapid IL-8 production may play a critical role in the rapid rise in temperature following administration of large doses of adenovirus, as observed in this paper. In the present study, it was found that, with doses below 2·5x108 p.f.u. adenovirus, fever curves showed a longer lag period, a lower peak level of temperature and a longer period of time to reach the peak temperature. The decrease in the peak temperature and the prolongation of the period to reach the peak temperature were dependent on the dose of adenovirus. The results suggest that high concentrations of adenovirus are required to release endogenous pyrogen efficiently from phagocytes and that, at concentrations below a certain limit, the effect of adenovirus on the release of endogenous pyrogen is decreased markedly. One of the previous studies that failed to detect pyrogenicity of adenovirus used extracts of HeLa cells infected with adenovirus type 4 for injection into rabbits, but their virus titres were not described (King, 1962 ). The other studies used adenovirus type 2, but detailed experimental conditions were not given (Siegert, 1967 ; Grossgebauer, 1967 ). Judging from the results of the present study, the virus doses used in these earlier studies must have been sub-optimal for pyrogenicity.

Adenovirus types 3, 5 and 8 are antigenically distinct from each other. The pyrogenicity of adenovirus types 3, 5 and 8 was never neutralized by homologous antiserum. Pyrogenic cross-tolerance could be established between every combination of these types. These findings suggest that the virion component(s) responsible for pyrogenicity does not correspond to any type-specific antigen and seems to be common to different adenovirus types, at least types 3, 5 and 8. The pyrogenicity of adenoviruses was not inactivated by UV irradiation, in contrast to infectivity, but both pyrogenicity and infectivity were inactivated by heating at 56 °C for 30 min. The simplest conclusion derived from the heat lability of adenovirus pyrogenicity is that the pyrogenic virion component(s) is easily inactivated by heating at 56 °C for 30 min. However, it was found that, when adenovirus type 5 was heated at 56 °C, the icosahedral capsid of the virion is ruptured at the twelve vertices (Russell et al., 1967 ). If the behaviour of adenovirus types 3 and 8 on heating is similar to that of type 5, the finding that adenoviruses lose pyrogenic activity when heated at 56 °C may also support the hypothesis that the complete structure of the virion is needed for its action as a pyrogen. Influenza virus pyrogenicity was shown to depend upon the integrity of virions, but haemagglutinin and/or neuraminidase appear to be essential and lipid may be involved (Pickering et al., 1992 ; Alluwaimi et al., 1994 ).

In contrast to the high dose (109 p.f.u.) of adenovirus required to exhibit a definite febrile response, a much lower dose (107 p.f.u.), that is one that is non-pyrogenic in itself, became highly pyrogenic in the presence of homologous type-specific antibodies at an optimal virus:antibody ratio. The pathogenesis of the febrile response in humans infected with adenovirus may involve two different kinds of mechanism; one that depends upon the pyrogenic activity of virions and the other that depends upon the pyrogenic activity of the virus–antibody complex. From the results of the present study, however, it is probable that the latter mechanism is the main contributor to fever in adenovirus infection under actual physiological conditions.


   Acknowledgments
 
I am indebted to Michio Ohta and Setsuko Naito for their assistance in this work, to Hideo Ito for preparing the manuscript and to Eiichi Hayashi for drawing the figures.


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Received 27 June 2000; accepted 7 August 2000.



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