Poxviruses Affecting Humans PDF

Journal of Clinical Virology 174 (2024) 105719 Contents lists available at ScienceDirect Journal of Clinic...

Journal of Clinical Virology 174 (2024) 105719 Contents lists available at ScienceDirect Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv What the pox? Review of poxviruses affecting humans D.Jane Hata a, * , Eleanor A. Powell b , Meghan W. Starolis c , Susan E. Realegeno d a Department of Pathology and Laboratory Medicine, Mayo Clinic Florida, 4500 San Pablo Rd., Jacksonville, FL 32224 USA b Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 234 Goodman St., Cincinnati, OH 45219, USA c Quest Diagnostics,14225 Newbrook Dr., Chantilly, VA 20155, USA d Quest Diagnostics, 33608 Ortega Highway. San Juan Capistrano, CA 92675 USA A R T I C L E I N F O A B S T R A C T Keywords: The re-emergence of human mpox with the multi-country outbreak and a recent report of borealpox (previously Poxvirus Alaskapox) resulting in one death has heightened awareness of the significance of the Poxviridae family and their Mpox zoonotic potential. This review examines various poxviruses affecting humans, with discussion of less commonly Orthopoxvirus encountered Poxviridae members, including pathogenesis, epidemiology, and diagnostic methods. Poxvirus Zoonotic poxviruses treatment is beyond the intended scope of this review and will not be discussed. 1. Introduction Asfarviridae viral families. Among OPXVs, cowpox virus (CPXV) has the most conserved genome, as other OPXV species contain point mu- The family Poxviridae consists of large, double-stranded, enveloped tations, deletions, and rearrangements which delineate them from the DNA viruses with 10 significant genera in human disease [1,2]. original progenitor CPXV sequence. Although members of the Orthopoxvirus (OPXV) genus are commonly cited, less frequently encountered genera such as Parapoxvirus, Yata- 2.2. Pathogenesis poxvirus, and Molluscipoxvirus have clinical significance. All poxviruses exhibit two distinct infecting particles – the mature virion and envel- OPXVs exhibit significant variability of host cell tropism and host oped virion. Disease manifestations vary from self-limiting localized range. The cytopathic effect observed in OPXV-infected cells is a dermal nodules in Molluscipoxvirus infections to high morbidity and manifestation of rearrangement of host cell cytoskeletal components due mortality associated with human smallpox, caused by variola virus to viral replication. Although a single specific host cell receptor for (VARV). Some members of Poxviridae are zoonotic, presenting risk of poxviruses has not been identified, several glycosaminoglycans and human infection via exposure to wild or domesticated mammals. This laminins have been demonstrated to mediate adsorption of OPXV into review discusses the four genera of Poxviridae in terms of structure, susceptible cells. pathogenesis, epidemiology, and diagnostic methods. Transmission of OPXV occurs primarily via exposure to skin lesions, respiratory droplets, aerosols, animal scratches, or fomites containing 2. Orthopoxvirus genus virus. OPXV infections generally present as a macular rash or lesions progressing through vesicular and pustular stages with occasional ul- 2.1. Structure cerations and epidermal hyperplasia. Intracytoplasmic inclusion bodies can be noted within tissue keratinocytes. Orthopoxviruses are among the largest mammalian viruses known Lesions may occur in oropharyngeal, ocular, or mucocutaneous sites. (240 × 300 nm) [2,4,5]. The complex internal structure consists of two Genital and anorectal infections have been a hallmark of the recent lateral bodies and a dumbbell-shaped nucleosome with a genome mpox outbreak. Lesions typically develop simultaneously on a given approximately 130 – 260 kb length. The large brick-shaped viral parti- part of the body and may be singular or multiple [8,9], eventually cles are encased with palisading surface tubules surrounded by a fragile developing crusts with desquamation over several weeks. Systemic outer envelope upon release from infected host cells. Replication symptoms may include fever, chills, lymphadenopathy, cough, and occurs solely in the host cell cytoplasm, notable among Poxviridae and conjunctivitis. Leukocytosis, thrombocytopenia, and liver enzyme * Corresponding author at: Department of Pathology and Laboratory Medicine, Mayo Clinic Florida. 4500 San Pablo Rd., Jacksonville, FL 32224 USA. E-mail address: [email protected] (D.Jane Hata). https://doi.org/10.1016/j.jcv.2024.105719 Received 21 May 2024; Received in revised form 31 July 2024; Available online 5 August 2024 1386-6532/© 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies. D.Jane Hata et al. Journal of Clinical Virology 174 (2024) 105719 reservoir for infection, which are arboreal African rodents. As a wide variety of OPXVs have been identified in vertebrate hosts, reservoir populations have the potential to provide a platform for zoo- notic transmission to humans, with VACV, CPXV, and MPXV commonly cited. Most zoonotic outbreaks are relatively limited in terms of size and scope with low mortality. However, the mpox outbreak of 2022 resulted in over 88,000 cases and 140 deaths by the end of the global health emergency in May 2023. Prior to 2022, an increase in the number and magnitude of mpox outbreaks occurring in endemic regions had been observed [13,14]. Environmental/ecological influences, viral adaptation, and cessation of routine cross-protective smallpox vaccina- Fig. 1. Electron micrograph of Vaccinia (mulberry form) demonstating surface tion are suggested as contributors to the increased number of cases [13, tubular elements surrounding the brick shaped virion structure. Photo source: 14]. The first fatal case of borealpox in an immunocompromised host CDC Public Health Image LIbrary (PHIL). Home - Public Health Image Library (PHIL) (cdc.gov). was recently reported, and speaks to the need for ongoing OPXV awareness [15,16]. VARV carries great significance due to its historical impact, potential for rapid spread, and hypothetical use as a bioweapon. VARV was responsible for an estimated 300–500 million human deaths during the 20th century, impacting national economies, trade, and societal evolu- tion. Variola major can result in 30 % mortality, with Variola minor demonstrating a mortality rate of < 1 %. Through quarantine and vaccine deployment, natural transmission of VARV has been eliminated worldwide since 1980. Excellent reviews of OPXVs are provided in references [2,5,7,18] and in-depth reviews of MPXV are also available [9,11]. 3. Parapoxvirus genus 3.1. Structure The Parapoxvirus (PPV) genus contains 6 viruses: Orf (ORFV), grey sealpox (GSEPV), bovine papular stomatitis (BPSV), pseudocowpox virus, and red deerpox, all of which have been documented in human infection. PPVs are enveloped viruses that are generally ovoid in shape and are 240–300 nm by 140–190 nm [19,20]. They contain a 140 kb dsDNA genome containing more than 100 genes. 3.2. Pathogenesis All PPVs have a similar disease presentation in humans. Initially, one or a small number of dermal nodules develops after exposure to an infected animal. These nodules typically move through a mac- ulopapular, targetoid, acute, regenerative, papilloma, and regression stage [21-23]. Each stage lasts approximately one week, with healing in four to six weeks. Localized lymphadenopathy may occur, but systemic Fig. 2. HE stain of skin containing Variola lesion (Courtesy Dr. Bobbi Pritt). illness is rare and is generally limited to immunosuppressed hosts. In immunosuppressed patients, nodules may be larger and persist longer elevations are common.. Immunosuppressed patients (and rarely immunocompetent pa- tients) may also develop erythema multiforme [23-25]. While para- poxvirus disease is mild in immunocompetent individuals, accurate 2.3. Epidemiology diagnosis is essential to rule out other pathogens exhibiting overlapping symptoms. The OPXV genera includes vaccinia (VACV), cowpox (CPXV), cam- elpox, horsepox, borealpox (BRPV) and mpox (MPXV) viruses, which 3.3. Epidemiology affect humans and multiple wild or domestic mammals, and VARV, affecting only humans. Edward Jenner first used CPXV in 1796 to induce PPVs typically occur worldwide without geographic restriction. Each VARV immunity.VACV has been used to vaccinate individuals PPV has a distinct host reservoir and risk group. For instance, pseudo- against smallpox since the 19th century [2,5]. OPXVs are commonly cowpox is the causative agent for milker’s nodules, causing lesions on named after their zoological source of isolation, which may or may not the udders and mucous membranes of cows, and infections in dairy be their natural reservoir; misalignment with the actual reservoir host or workers [21,27]. BPSV also occurs in cows and has been associated with host range has contributed to confusion with the true origin of a given their handlers, but it does not cause visible lesions in cows. ORFV is virus and/or its geographical distribution. For instance, mpox, pre- the causative agent for ecthyma contagiosum in humans. It causes viously known as “monkeypox” was recently renamed to remove papules, vesicles, and pustules around the mouth and nose of goats and zoological and geographic references in efforts to reduce associated sheep. Transmission to humans has been associated with veteri- stigmas. The name “monkeypox” was a misnomer since it was originally narians, butchers, sheep shearers, and petting zoo attendees. discovered in primates housed in a research facility and not the primary GSEPV is found in grey and harbor seals, and transmission to humans is 2 D.Jane Hata et al. Journal of Clinical Virology 174 (2024) 105719 Table 1 Summary of selected poxviruses associated with human infection. Genus Virus Size of Virus Size of complete Host Range Reservoir Host Transmission Disease Particle Viral Genome Orthopoxvirus Variola 240 × 300 nm 130 - 260 KB Humans Humans Contact, respiratory Smallpox droplets, fomites Vaccinia Approximately 200 Multiple, including Rodents Contact, respiratory Generalized KB humans droplets, fomites vaccinia, Vaccinia eczematum Cowpox 220 - 222 KB Humans, cattle, Rodents Contact Cowpox rodents, cats Camelpox 205 KB Humans, camels Dromedary camels Contact, fomites Camelpox MPOX Approximately 200 Humans, various Unknown; likely Contact, fomites, MPOX KB primates, rodents, arboreal rodents droplets squirrels Parapoxvirus Orf (ORFV) 240–300 × Approximately 140 Humans, goats, Goats and sheep Contact Orf 140–190 nm kb and sheep Bovine papular Humans, cows Cows Bovine papular stomatitis virus stomatitis (BPSV) Grey Sealpox virus Humans, grey and Seals Sealpox (GSEPV) harbor seals Pseudocowpox Humans, Cows Cows Milker’s nodule Red Deerpox Humans, deer Deer Deerpox Yatapoxvirus Tanapoxvirus 280 nm x 220 145 KB Humans, various Unknown Unknown, but Tanapox nm primates suspected vector borne [36,37] Molluscipoxvirus Molluscum 320 nm × 250 190 KB Humans Humans Contact, fomites Molluscum contagiosum virus nm × 200 nm contagiosum (MCV) Genus Virus Clinical Symptoms Disease Mortality (human) Biosafety Level Diagnostic Vaccine Available Duration (Clinical Methods* Specimens) Orthopoxvirus Variola Rash, macules, vesicules, 24 h (death) Variola major − 30 % BSL 4 (CDC and Species- specific ACAM 2000, pustules -to 2–3 weeks Variola minor -< 1 % public health NAAT, OPXV JYNNEOS (both labs only) antibody detection Vaccinia strains) Vaccinia Rash, macules, vesicules, 4 − 6 weeks 0.0001 %: routine BSL-2 Species- specific Vaccine strain pustules, (human) vaccination 1 %: NAAT, OPXV lymphadenopathy eczema vaccinatum 33 antibody detection %: vaccinia necrosum Cowpox Hand lesions, 2 - 4 weeks Not reported BSL-2 Species- specific Cross protection lymphadenopathy, fever NAAT, OPXV possible with antibody detection vaccina virus vaccines Camelpox Fever, hand lesions, nasal 4 - 6 weeks Up to 25 % BSL-2 Genus-level NAAT Cross protection discharge, GI, respiratory possible with distress vaccina virus vaccines MPOX Lesions, fever, 4 weeks Clade I ~ 10 % Clade II BSL-2 with Species and clade JYNNEOS, cross- lympadenopathy, hepatic ~1% enhanced specific NAAT, protection with necrosis precautions OPXV antibody ACAM2000 detection Parapoxvirus Orf (ORFV) Lesions, localized 4–6 weeks Not Reported BSL-2 Species- specific No lymphadenopathy NAAT Bovine papular Species- specific stomatitis virus NAAT (BPSV) Grey Sealpox virus Species- specific (GSEPV) NAAT Pseudocowpox Species- specific NAAT Red Deerpox Genus- level NAAT Yatapoxvirus Tanapoxvirus Fever, lesions 6 weeks Not reported BSL-2 Species- specific No NAAT Molluscipoxvirus Molluscum Pearly pink or white 6–9 months Not reported BSL-2 Species- specific No contagiosum virus rounded papules typically but as NAAT (MCV) long as 3–4 years EM: Electron microscopy, NAAT: Nucleic Acid Amplification Test, IHC: Immunohistochemistry. * EM, IHC, sequencing may be used for all genera. 3 D.Jane Hata et al. Journal of Clinical Virology 174 (2024) 105719 associated with seal handlers and trainers. In some cases infections 5.2. Pathogenesis in humans have resulted from seal bites. Red deerpox virus causes disease in red deer and infection has been noted in deer hunters. As MCV infects epidermal keratinocytes which play a crucial role in skin the clinical features of infection are typically mild and self-limiting, repair and protective immunity [42,46]. Children ages 2–5 are most cases are likely underreported. affected and present with pearly pink or white rounded papules measuring approximately 2–5 mm on areas of exposed skin except the 4. Yatapoxvirus genus palms and soles. Lesions on the face, trunk, extremities, skin folds, and genital area are usually from self-inoculation. Typically, the patient 4.1. Structure has between 1 and 20 painless papules which have a characteristic central dimple. Transmission in adults is mainly through sexual The yatapoxvirus group contains Yaba monkey tumor virus (which contact with lesions present in genital and perianal regions. Skin does not infect humans) and Tanapoxvirus (TPV). Yaba-like disease lesions are self-limiting but can last for long periods of time, usually virus is described in the literature, but is likely the same virus as TPV between 6 and 9 months but may take 3–4 years for resolution.. TPV is an enveloped brick-shaped virus that is approximately 280 nm by 220 nm with a 145 kb linear genome [33,34]. Studies of TPV 5.3. Epidemiology show experimental infection in primary human dermal fibroblasts and monocytes but no replication in lymphocytes. Inability to replicate MCV is species-specific to humans and ubiquitous worldwide but in lymphocytes as well as improved replication at 35 ◦ C as compared to may be more prevalent in warm geographic areas. The virus is 37 ◦ C (i.e., below human body temperature) may contribute to lack of spread person-to-person or via contaminated fomites. A systemic symptoms during infection. meta-analysis to understand global prevalence data showed an 8.28 % overall prevalence but was skewed by three high prevalence MCV re- 4.2. Pathogenesis ports (New Guinea at 21.8 % , Israel at 34.6 % , and Japan at 19.7 % [51,52]. With these outliers removed, prevalence was calculated TPV infection is characterized by a short febrile illness of 3–4 days at 2.8 %. The overall prevalence in the United States is estimated to with headache, backache and singular lesions. Vesicles are smallpox-like be 5.0 % [45,53]. Transmission of MCV can be observed year-round with and follow a similar disease course, but lesions are larger, firmer, and notable hot spots of transmission within daycares and schools. evolve slowly. In the largest documented outbreak, 77 % of lesions were on the front or lower body, 79 % were on areas not covered by 6. Diagnostic methods for poxvirus infections clothing, and 78 % were single lesions. Lesions are preceded by itching before erupting as a large (approximately 10 mm) macular lesion that 6.1. Biosafety may become nodular during the first week. Lesions are typically accompanied by regional lymphadenopathy, may ulcerate, and enlarge Clinical specimens submitted for high-risk agents, such as VARV or for 2 to 3 weeks before spontaneously resolving within 6 weeks. MPXV Clade I viruses that are unfixed or not inactivated should be handled in a BSL-3 or higher facility by vaccinated personnel and 4.3. Epidemiology preferably referred to a public health laboratory. Vaccinated individuals can perform work with replication-competent VACV and other human TPV was first identified in a small outbreak among children poxviruses in BSL-2 facilities. Additional safety practices and equipment attending a single school in the Tana River valley (Kenya) in 1957, can be considered based on a site-specific risk assessment [3,54]. followed shortly by a 50-case outbreak in 1962. Both outbreaks Routine virus isolation or propagation of virus from clinical samples followed large floods, which created swamps and isolated communities. should not be attempted in clinical laboratories. VARV and MPXV Clade By 1971, 16.3 % of Tana River valley residents had serologic evidence of I are listed as select agents and subject to subsequent reporting and infection indicative of ongoing transmission. Subsequent surveil- inactivation/destruction as outlined by the Federal Select Agent Pro- lance in the Congo River valley found 357 TPV cases from 1979 to 1983, gram. Positive samples identified by MPXV Clade II specific NAATs are most within a 9-month period in 1980–1981. In this outbreak, 57 % not subject to select agent regulations. of cases were in patients who lived within 300 m of a recent case, 20 % had a neighbor who was also infected, and 25 % lived in the same 6.2. Diagnostic methods household as another infected person. Due to the association with floods and mosquito season, it is presumed that TPV is a mosquito-borne dis- Initial clinical suspicion for infection is determined by symptom ease, though this has never been experimentally proven [36,37]. Beyond presentation. Since poxvirus infections are uncommon, laboratory the Tana and Congo river valleys, TANV has also been detected in South testing should be based on epidemiologic risk factors and in consultation Africa , a European traveler returning from Tanzania , a New with the public health department. Epidemiologic risk factors may Hampshire college student after caring for chimps in the Republic of include travel history to endemic areas, contact with a potentially Congo , and among imported macaques and their handlers in Texas, infected person or animal, or recent vaccination history with California, and Oregon [32,41]. ACAM2000, the smallpox vaccine comprised of replication competent vaccinia virus. Diagnostic testing of poxviruses in the United States is 5. Molluscipoxvirus genus limited to public health laboratories, except for MPXV which is also available in some hospital and commercial laboratories. In addition to 5.1. Structure evaluating risk factors, characterizing dermatologic lesion appearance and progression is one of the key determinants for performing poxvirus The genus Molluscipoxvirus has only one species, Molluscum con- specific testing. ORFV and MCV infections can be diagnosed without the tagiosum virus (MCV), which is responsible for a skin infection commonly need for laboratory testing, while other poxviruses infections generally seen in children. The virion shape has been described as oval or require confirmation. Laboratory testing may also be indicated when brick-shaped, measuring approximately 200 - 300 nm. This lesions have an atypical appearance or cannot be differentiated from enveloped virus encodes for approximately 160 proteins and is other infectious and non-infectious etiologies causing a rash illness. approximately 190 kb in size. There are four recognized subtypes A specialized algorithm for evaluating patients suspected of smallpox (I/Ia, II, III, and IV) with type I being the most prevalent [42,44,45]. presenting with an acute, generalized vesicular or pustular rash illness 4 D.Jane Hata et al. Journal of Clinical Virology 174 (2024) 105719 has been developed. The clinical algorithm classifies patients into specific detection of OPXV, PPV, and Yatapoxviruses. A high, moderate, and low risk categories to strategically guide diagnostic pan-poxvirus assay has also been developed and used for screen- testing to rule out other common infectious causes (e.g. varicella-zoster) ing/identification of novel poxviruses in the Chordopoxvirinae subfamily before initiating VARV-specific testing. This reduces the risk of unnec- [2,64]. Several species-specific assays are available within the OPXV essary testing that may lead to false-positive results in the context of and PPV genera, while TPV is the primary species available within the disease eradication, but still allows for consideration of a potential Yatapoxvirus genus. An MCV-specific PCR assay is also available. bioterrorism event and the intentional release of VARV. An OPXV. Available OPXV specific assays include VARV, non-VARV, VACV, laboratory testing algorithm is available for patients suspected of a MPXV (generic and clade specific), and CPXV. Parapoxvirus specific as- smallpox vaccine adverse event related to ACAM2000 or inadvertent says available include ORFV, pseudocowpox virus, BPSV, and GSEPV infection from close contact with a person’s vaccination site.. Laboratory diagnostic methods for identifying and differentiating During the 2022 global mpox outbreak, some clinical laboratories poxviruses have traditionally included virus isolation via cell culture, implemented PCR-based assays as laboratory developed tests targeting antigen testing, and electron microscopy (EM). However, direct detec- OPX, non-variola OPX, or MPXV (generic or clade specific) genes. tion using nucleic acid amplification tests (NAATs) are preferred as they Commercially available NAATs for OPXV and MPXV are also available are rapid with high sensitivity and specificity. Genome sequencing has under FDA emergency use authorization status. An OPXV real-time PCR also become an important tool for molecular epidemiology, as it can primer and probe set was previously FDA approved for use in designated differentiate variants and identify resistance mutations in addition to Laboratory Response Network (LRN) laboratories and was recently species identification. Specimens submitted for initial testing include authorized for use in select commercial reference laboratories [66,67]. lesion material or fluid, which often contain a high viral burden depending on the stage of the lesion. Vigorously swabbed lesions, 8. Conclusion exudate or vesicular/pustule fluid, scab or crusts are also acceptable. Deroofing of crusts or fluid aspiration is not required and may pose an As presented in this review, continual evolution in the emergence infection risk for the specimen collector. and pathogenesis of Poxviridae family require ongoing surveillance ef- forts, in addition to enhancement of diagnostic methods. Clinical labo- 6.2. Serology Testing ratories are encouraged to remain vigilant to best assess Poxviridae epidemiology and participate as active partners with medical providers Antibody detection may be used to support diagnosis, evaluate in patient care and assessment. exposure or immune status, or for serosurveillance. In the absence of Table 1 lesion specimens, acute and convalescent sera can be collected several weeks apart to document seroconversion. Species-specific antibody as- CRediT authorship contribution statement says are typically not offered due to significant cross-reactivity within the genera. An IgG/IgM ELISA using purified VACV is available for D.Jane Hata: Writing – review & editing, Writing – original draft, OPXVs through the CDC. Serology testing for other poxviruses is Investigation, Formal analysis, Data curation, Conceptualization. Ele- not readily available. anor A. Powell: Writing – review & editing, Writing – original draft, An OPXV IgG result alone may be indicative of vaccination, or pre- Investigation, Formal analysis, Data curation, Conceptualization. vious exposure/infection, whereas IgM can be detected soon after Meghan W. Starolis: Writing – review & editing, Writing – original infection in both vaccinated and unvaccinated individuals. Re- draft, Investigation, Formal analysis, Data curation, Conceptualization. sponses can be detected within a week after presentation of rash for both Susan E. Realegeno: Writing – review & editing, Writing – original IgM and IgG and IgG responses have been detected indefinitely in draft, Investigation, Formal analysis, Data curation, Conceptualization. vaccinated individuals [59,60]. Alternatively, serum neutralization tests using plaque reduction have been developed to assess immune responses Declaration of competing interest to OPXVs. Although a 4-fold increase in antibody titer between acute and convalescent sera can be diagnostic for infection, established The authors declare the following financial interests/personal re- thresholds correlated with protection against future infection have not lationships which may be considered as potential competing interests: been established. D. Jane Hata and Eleanor Powell report no financial conflicts of in- terest. Meghan Starolis and Susan Realegeno disclose they are full-time 6.3. Viral Isolation & microscopic identification: cell culture, employees and shareholders of Quest Diagnostics. immunohistochemistry (IHC), electron microscopy (EM) Funding Most poxviruses infecting humans will grow in a variety of cell lines and can exhibit cytopathic effects (CPE), except for MCV which cannot D. Jane Hata and Eleanor Powell report no financial conflicts of in- be propagated. EM can be used to identify the presence of a terest. Meghan Starolis and Susan Realegeno disclose they are full-time poxvirus in cultured specimens or directly from specimens due to its employees and shareholders of Quest Diagnostics. unique brick-shaped virion structure surrounded by irregular short tubular elements (Fig. 1). Histologic examination of lesion biopsy sam- ples stained with H&E or Giemsa stains can reveal perinuclear baso- Disclosures/Disclaimers philic or cytoplasmic round or oval inclusion bodies (Fig. 2). Acidophilic-type inclusion bodies can also be found with CPXV infec- This Report is a product of the Pan-American Society for Clinical tion. IHC can identify poxviruses only to the genus level using antibodies Virology (PASCV) Clinical Practice Committee (CPC) which was devel- against genus specific antigens. Overall, these methods can be useful in oped to provide guidance and recommendations to healthcare pro- identifying a novel poxvirus infection associated with a rash illness of fessionals. It is not clinical advice and is not intended to characterize all unknown etiology. possible disease presentations, diagnostic methods or treatment. 6.4. Direct Detection (NAAT) Ethical Approval Real-time qPCR assays are available through the CDC for genus Not required. 5 D.Jane Hata et al. Journal of Clinical Virology 174 (2024) 105719 Acknowledgments M. Birkhead, W. Grayson, A. Grobbelaar, V. Msimang, N. Moolla, A. 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