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Am. J. Trop. Med. Hyg., 75(6), 2006, pp. 1135-1139
Copyright © 2006 by The American Society of Tropical Medicine and Hygiene

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USE OF IgG AVIDITY TO INDIRECTLY MONITOR EPIZOOTIC TRANSMISSION OF SIN NOMBRE VIRUS IN DEER MICE (PEROMYSCUS MANICULATUS)

DAVID SAFRONETZ, ROBBIN LINDSAY, BRIAN HJELLE, RAFAEL A. MEDINA, KATY MIROWSKY-GARCIA, AND MICHAEL A. DREBOT*
Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada; Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada; Center for Infectious Diseases and Immunity, Departments of Pathology, Biology, and Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
An IgG avidity assay was developed to differentiate deer mice that had recently acquired Sin Nombre virus (SNV) from those that were infected in the distant past. Using this procedure, low avidity antibodies were predominantly detected in experimentally infected deer mice (89.5%) within the first 30 days post-inoculation. The assay was then applied to sera from naturally infected deer mice collected during a field investigation associated with a cluster of hantavirus pulmonary syndrome cases. A higher proportion of seropositive mice collected during the outbreak had serum with low avidity antibodies (16.7%) when compared with mice trapped four months later (5.7%). Sin Nombre virus RNA was detectable in blood in a similar fraction of low- (45%) and high- (38.7%) avidity groups. Non-adult mice were more likely to contain low-avidity antibodies (44.4%) than were adults (9.6%). Our results indicate that the IgG avidity assay shows promise as a tool to better characterize epizootic intensity and to identify factors involved in SNV transmission.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sin Nombre virus (SNV) is a rodent-borne pathogen belonging to the genus Hantavirus within the family Bunyaviridae. In North America, SNV is the predominant etiologic agent of hantavirus pulmonary syndrome (HPS), a relatively rare but often fatal disease of humans.1 In nature, the deer mouse (Peromyscus maniculatus) is the natural reservoir for SNV. Once infected, SNV establishes a chronic infection with no obvious deleterious effects on the rodent.2 Similar to other hantaviruses, transmission of SNV between rodents, and to humans, is believed to occur through contaminated secreta and excreta. However, it is still unclear at what stages of infection mice shed virus, and if any environmental or host factors influence viral transmission.

As of July 10, 2006, 62 cases of HPS have been identified in Canada (Feldmann H, unpublished data). Most of these occurred as single cases, with few communities reporting multiple cases of HPS in the same year. In May 2005, four laboratory-confirmed human cases of HPS occurred within a one-week period in a small prairie community in central Alberta, representing the first cluster of HPS cases in Canada.3 At that time, deer mice collected from the surrounding area had an unusually high seroprevalence of SNV. Four months after the cluster of cases, the seroprevalence in deer mice from the same areas had decreased (Lindsay R, unpublished data). The aim of the studies reported here was to determine whether this cluster of HPS cases occurred concomitantly with an increased proportion of recently infected deer mice.

To help determine the duration of SNV infection in deer mice and to differentiate between recently and remotely infected rodents, an IgG avidity assay was used. IgG avidity assays have been used for the diagnosis of many human pathogens, including hanatavirus infections, as well as for estimating Puumala virus infection onset in wild bank voles.4–6 These assays are based on the observation that antibody avidity increases with time after exposure to an immunogen.7 Avidity assays rely on a protein denaturant that can disrupt the antibody-antigen complex affecting low-avidity antibodies, but not high-avidity antibodies. Based on this principle, the presence of low-avidity antibodies in a serum sample is indicative of a recent infection and high-avidity antibodies indicate that the infection occurred in the distant past.


MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
IgG avidity assay. The methodologies used in the IgG avidity assay are based on a previously established indirect enzyme-linked immunosorbent assay (ELISA) that uses a recombinant SNV nucleocapsid (N) antigen for the detection of specific IgG antibodies.8 Briefly, serum samples were diluted 1:100 in phosphate-buffered saline (PBS) supplemented with 0.5% Tween 20 and 5% skim milk and tested in duplicate in ELISA plates previously coated with the SNV N antigen. After incubation at 37°C for 60 minutes, sample wells were washed with PBS with 0.1% Tween 20 (PBS-T), and treated with either a 35 mM diethylamine (DEA; Sigma-Aldrich, Oakville Ontario, Canada) denaturing solution or with PBS-T, three times (five minutes per treatment). After the DEA treatments, all wells were washed an additional six times with PBS-T, before incubation with peroxidase-labeled anti-rodent (a mixture of goat anti-P. leucopus and goat anti-rat, 1:2,000 each; Kirkegaard and Perry Laboratories, Gaithersburg, MD) secondary antibodies (60 minutes at 37°C), and addition of substrate (2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) peroxidase substrate; Kirkegaard and Perry Laboratories) for 30 minutes. Color development was quantified by reading the optical density at 405 nm (OD405). The relative avidity index (RAI) was calculated by dividing the OD405 of the DEA-washed wells by that of the wells washed with PBS-T and expressed as a percent (RAI = OD405 DEA/OD405 PBS-T) x 100). Samples with an RAI ≥ 40% were considered low avidity and samples with an RAI ≥ 60% were considered high avidity. Samples with an RAI between 40% and 60% were considered intermediate.

Assay validation. A total of 60 serum samples from both naturally (n = 29) and experimentally (n = 31) infected deer mice were blind-tested to assess the utility of the avidity assay in identifying recently infected deer mice. Four to eight-week-old deer mice (P. maniculatus rufinus) were experimentally infected (intramuscular inoculation) with 10–25 infectious dose-50 of SNV strain SN77734 as previously described, and humanely killed between days 14 and 217 post-infection.9,10 Mice were humanely killed with ketamine/xylazine and blood samples collected by cardiac puncture. Samples from naturally infected deer mice were available from past and present field studies conducted in Canada, as described elsewhere.11,12 Captured animals had been anesthetized by inhalation of isoflurane and bled by the retro-orbital sinus using blood collection tubes.

Laboratory animals were handled according to the University of New Mexico animal research facility guidelines using approved protocols. Field-collected animals were handled in compliance with guidelines established by the Canadian Council of Animal Care and using protocols approved by the Canadian Science Center Animal Care Committee.

Measuring the epizootic intensity. In May 2005 a cluster of human cases of HPS were identified in a small prairie community in Alberta, Canada (referred to as community A). As part of a risk-assessment protocol, deer mice were collected from community A as well as from areas around a second community (B) that had no reported cases of HPS and was located within 20 km of community A, both at the time of the outbreak (May) as well as in September 2005 as part of a follow-up study (field studies to be described elsewhere). A total of 163 serum samples reactive for hantavirus-specific IgG at a dilution ≥ 1:100 were used to measure the epizootic intensity of SNV in deer mice collected at either of the two time points. Where sufficient blood volumes were available, whole blood samples were tested for the presence of hantavirus-specific RNA using a nested reverse transcription–polymerase chain reaction as previously described.8 Chi-square tests were performed using the statistical software package SAS version 9.1 (SAS Institute, Cary, NC) to test for differences in age, sex, and viremia between the high- and low-avidity groups.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Assay validation. We conducted the avidity assay on coded samples from experimentally infected deer mice and characterized the results according to the likelihood that samples were collected acutely after experimental infection or during a later phase of infection. The reactivity (binding of deer mouse IgG to SNV N protein) of sera collected from experimentally infected animals within 30 days post-inoculation (dpi) was greatly reduced by the addition of the denaturant (DEA), resulting in an RAI ≤ 40% and indicating the presence of low-avidity antibodies (Figure 1Go). The average RAI of samples collected 10 and 20 and 21 and 30 dpi was 9.3% and 19.9%, respectively. However, the reactivity of most sera collected ≥ 30 dpi was only modestly affected by the denaturant, as demonstrated by an RAI ≥ 60% (Figure 1Go). Samples collected ≥ 40 dpi had an average RAI of 85.7%. No serum collected from an experimentally infected animal at a time point > 35 dpi had an RAI ≤ 40% and no sample collected < 34 dpi had an RAI ≥ 60%. The average RAI of samples collected between 31 and 40 dpi was 70%. Our results were 89.5% accurate in distinguishing samples collected during the first 30 dpi.


Figure 1
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  		    FIGURE 1. Comparison of avidity indices of serum samples collected from experimentally infected deer mice.

 
Similar observations were made with a sub-set of sera collected from naturally infected deer mice with documented seroconversion. Paired serum samples documenting seroconversion and collected within 21 days of each other contained low-avidity antibodies, with an average RAI of 25.3%. However, samples collected from deer mice with seroconversion occurring at greater than 40 days were predominantly high avidity, with an average RAI of 80%. After detection of high-avidity antibodies in an adult mouse, all subsequent samples collected contained high-avidity antibodies.

Measuring epizootic intensity. One hundred twenty IgG-positive serum samples collected in May (108 from community A and 12 from community B) and 43 positive samples collected in September (35 from community A and 8 from community B) were tested for high- or low-avidity antibodies. The avidity profiles of deer mice collected over the two sampling periods from the two communities are summarized in Table 1Go. A higher proportion of deer mice with low-avidity antibodies were detected in both communities in the May sampling period (16.7% and 8.3%, respectively, for communities A and B). In September, the proportion of mice with low-avidity antibodies decreased to 5.7% and 0% in communities A and B respectively. Because of the small number of samples from community B, a valid statistical comparison between avidity profiles from deer mice collected in communities A and B could not be completed. Additionally, low numbers of deer mice collected from community A in September reduced the power of statistical comparisons between the two time points in community A. However, there was a trend towards a higher proportion of deer mice with low avidity antibodies sampled in May from community A when compared with September (P = 0.10).


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TABLE 1
Comparison of avidity profiles from deer mice collected from two Alberta, Canada communities in May and September 2005
 
Over the two sampling periods, there was no significant difference in the proportion of blood samples with detectable SNV RNA between the low-avidity (9/20, 45%) and high-avidity (43/111, 38.7%) groups in deer mice sampled from community A (P = 0.19, Table 2Go). None of the deer mice with an intermediate avidity result had detectable SNV RNA in blood (0 of 7).


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TABLE 2
Comparison of antibody avidity and presence of Sin Nombre virus (SNV)–specific RNA in whole blood samples from deer mice collected from community A in May and September 2005
 
Comparison of avidity and deer mouse age structure demonstrated that non-adult deer mice (juvenile and sub-adult) were more likely to have low-avidity antibodies (P = 0.0013). Combining the two sampling periods, 8 (44.4%) of 18 non-adult deer mice collected in community A had low-avidity antibodies compared with 12 (9.6%) of 125 adult deer mice (Table 3Go). No significant difference was observed between sex of deer mice from community A and the presence of low-avidity antibodies. (P = 0.61).


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TABLE 3
Comparison of antibody avidity and age of infected deer mice collected in community A in May and September 2005*
 

DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Functional affinity (antibody avidity) has been previously used to characterize Old World hantavirus infections in both humans and rodent hosts.4–6 However, to our knowledge, this is the first study to apply these methods to naturally infected deer mice collected during an HPS field investigation. Most field studies use serologic positivity as a surrogate for infection in deer mice populations with SNV seroprevalence ranging up to nearly 50% at certain sites (Lindsay R, unpublished data).3,12–15 Although several factors have been epidemiologically linked to HPS cases, rodent population size and seroprevalence levels are most often used in field studies as estimates for the potential risk of humans acquiring HPS.16 However, seroprevalence determined by the presence of hantavirus-specific IgG antibodies does not provide an accurate assessment of viral transmission and overall risk of contracting HPS. Seropositive deer mice could differ in their infectiousness at any one time based upon if, and to what degree, virus is shed in excreta and/or secreta. If recent seroconversions correlate with increased probability of viral excretion, then use of IgG avidity as a means to monitor the epizootic intensity (i.e., monitoring virus transmission rates) of SNV in a given population of deer mice could provide a more accurate measure of risk than seroprevalence alone.

The time to appearance of high-avidity antibodies in deer mice experimentally infected with SNV is similar to those reported for bank voles experimentally infected with Puumala virus.6 Low-avidity antibodies (as defined by an RAI ≤ 40%) were predominantly documented in sera collected at time points less than 30 dpi. By 40 dpi, most experimentally infected deer mice tested had high-avidity antibodies (defined by an RAI ≥ 60%), with the remainder having intermediate avidity. Based on the transition of low-avidity to high-avidity antibodies (between 30 and 40 days), the IgG avidity assay reliably identifies deer mice that have been infected within approximately one month (30 days), at least on the population level.

Laboratory studies have suggested that hantavirus transmission may be highest in the early stages of infection based on increased detection of viral antigen and/or virus in numerous tissues shortly after infection.17 To better understand hantavirus transmission in natural settings, it would be of value to identify and differentiate recently infected deer mice from those that acquired infection in the distant past. Previously, Netski and others attempted to define stages of infection (i.e., acute or chronic infection) of deer mice based on patterns of serology and the detection of SNV RNA in blood.18 It has been suggested that a positive serologic result coupled with the detection of hantavirus-specific RNA in blood samples from rodents is indicative of a recent infection.18 Our findings do not support this diagnostic algorithm as a reliable method for identifying recently infected deer mice. We found that the detection of SNV RNA in blood samples does not predict the presence of low-avidity antibodies. In this study, if one considers all the deer mice collected from community A that had low-avidity antibodies as recently infected, the positive predictive value for the detection of SNV RNA in blood samples from seropositive mice as an indication of a recent infection is only 17%. This finding is not surprising in light of the recent observations of Kuenzi and others, who demonstrated that the detection of SNV RNA in blood samples collected over time from naturally infected deer mice was variable and not consistently positive or negative.15 Alternating patterns of detectable SNV RNA in blood are also observed in experimentally infected deer mice (Mirowsky-Garcia K and Hjelle B, unpublished data).2 The hypothesis of viral recrudescence or reactivation may serve as a basis for observations of the large proportion of deer mice with both high-avidity antibody and detectable SNV RNA in blood samples.

Non-adult (juvenile and sub-adult) deer mice were more likely to have low-avidity antibodies then adult deer mice (44.4% compared with 9.6%). However, we cannot rule out the possibility of residual maternal antibodies in these mice. The presence of maternal antibodies may also explain the small proportion of non-adult deer mice with high-avidity antibodies. Although it is possible that these mice were infected in the past, it is more likely that at least some of these mice are uninfected mice with residual maternal antibodies because they may not be old enough to have generated high-avidity antibodies through the normal infection route.19 Several studies have demonstrated that male deer mice are more likely to be seropositive than female deer mice.13,14 Our observations of roughly equivalent proportions of male and female deer mice with low-avidity antibodies suggest that despite this sex bias towards a higher proportion of infected males, both sexes are equally susceptible to SNV infection in at least some populations. This observation may also be supported by other studies that have documented similar incidence rates between the two sexes in some populations of deer mice.20

Cases of HPS have been epidemiologically linked with several possible risk factors including rodent infestation, handling wild rodents, and inhalation of aerosolized rodent excreta, as well as increases in rodent population size and seroprevalence rates.21 Many of these risk factors were also identified through field and epidemiologic studies in the recent cluster of human cases of HPS in Alberta.3 Our data also suggests that at the time of the HPS cases there was a trend towards a relatively greater prevalence of new infections in deer mice, as determined by a higher proportion of deer mice with low avidity antibodies collected at the time of the cases. We speculate that the cause of increased transmission among rodents was a function of population size and infection (based on seroprevalence); however, we cannot rule out yet unidentified factors such as viral, host, or environmental stresses or influences.16 The differentiation of recently infected mice from those infected in the distant past, if applied to future studies, may help clarify some of these factors (e.g., seasonal differences in transmission). Although the current study is unable to address the basis of heightened transmission between rodents, and to humans, it does demonstrate the utility of using an avidity assay to indirectly monitor viral transmission rates (by determining the proportion of recently infected mice), which can help assess the risk of humans contracting HPS.

Received April 26, 2006. Accepted for publication July 29, 2006.

Acknowledgments: We thank Antonia Dibernardo, Katarina Strank, and Michael Gray (National Microbiology Laboratory) for their technical assistance and Dr. Dan Chateau (Department of Community Health Sciences, University of Manitoba) for assisting with the statistical analysis.

Financial support: David Safronetz was supported by the Canadian Institutes of Health Research/International Center for Infectious Diseases/University of Manitoba training program in infectious diseases and the Manitoba Health Research Council. Brian Hjelle was supported by U.S. Public Health Service grant U01 AI 56618-01. Rafael A. Medina was supported by a Fogarty Actions for Building Capacity Award D43 TW01133.

* Address correspondence to Michael A. Drebot, Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, Manitoba R3E 3R2, Canada. E-mail: mike_drebot{at}phac-aspc.gc.ca Back

Authors’ addresses: David Safronetz, Department of Medical Microbiology, Room 543 BMSB, University of Manitoba, 730 William Avenue, Winnipeg, Manitoba R3E 0W3, Canada, Telephone: 204-789-7043, Fax: 204-789-2082. Robbin Lindsay and Michael A. Drebot, Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, Manitoba R3E 3R2, Canada, Telephone: 204-789-2000, Fax: 204- 789-2082. Brian Hjelle, Rafael A. Medina, and Katy Mirowsky-Garcia, Center for Infectious Diseases and Immunity, Department of Pathology, University of New Mexico, 329 CRF, MSC08 4640, 1 University of New Mexico, Albuquerque, NM 87131-0001, Telephone: 505-272-0624, Fax: 505272-4401.

Reprint requests: Michael A. Drebot, Zoonotic Diseases and Special Pathogens, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, Manitoba R3E 3R2, Canada, Telephone: 204-789-6059, Fax: 204-789-2082, E-mail: mike_drebot{at}phac-aspc.gc.ca.


REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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