Secondary diversification of the B cell repertoire by immunoglobulin gene somatic hypermutation in the germinal center (GC) is essential for providing the high-affinity antibody specificities ...required for long-term humoral immunity. While the risk to self-tolerance posed by inadvertent generation of self-reactive GC B cells has long been recognized, it has not previously been possible to identify such cells and study their fate. In the current study, self-reactive B cells generated de novo in the GC failed to survive when their target self-antigen was either expressed ubiquitously or specifically in cells proximal to the GC microenvironment. By contrast, GC B cells that recognized rare or tissue-specific self-antigens were not eliminated, and could instead undergo positive selection by cross-reactive foreign antigen and produce plasma cells secreting high-affinity autoantibodies. These findings demonstrate the incomplete nature of GC self-tolerance and may explain the frequent association of cross-reactive, organ-specific autoantibodies with postinfectious autoimmune disease.
Display omitted
► A new model that allows analysis of self-reactive B cells generated in the GC ► Self-reactive GC B cells are eliminated or inactivated by SHM ► Self-reactive GC B cells not eliminated if target self-antigen is in a distal tissue ► Explains postinfection production of cross-reactive tissue-specific autoantibodies
The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more ...severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed “mouse kidney parvovirus” (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.
Display omitted
•Inclusion body nephropathy is caused by mouse kidney parvovirus (MKPV)•MKPV is widely distributed in animal facilities in Australia and North America•MKPV is highly divergent from other mouse parvoviruses•Uncontrolled MKPV infection in immunocompromised mice results in renal failure
A kidney parvovirus found in multiple laboratory mouse colonies causes spontaneous nephropathy and represents a new tool for studying chronic kidney disease.
Mouse kidney parvovirus (MKPV) is a member of the provisional genus Chapparvovirus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated ...nephropathy in immune-suppressed kidney transplant patients. Here we map four major MKPV transcripts, created by alternative splicing, to a common initiator region, and use mass spectrometry to identify "p10" and "p15" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and the splicing-dependent putative accessory protein NS2 are conserved in all near-complete amniote chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that many mammal chapparvoviruses are likely to be nephrotropic.
The magnitude of impact of an invasive species on native taxa, and the time course of recovery, depend on the native’s ability to adjust to the invader. Here, we examine the impact of a toxic ...invasive prey species (cane toad
Rhinella marina
) on a vulnerable top-predator (lace monitor
Varanus varius
) in southern Australia. Lace monitor populations crash as soon as toads invade, as occurs in related species in tropical Australia. The toad’s impact falls primarily on larger lizards, such that mean body sizes decline precipitously after toad arrival. Feeding trials with free-ranging lizards clarified the reasons for that size-biased vulnerability. Large lizards attacked novel prey more rapidly than did smaller conspecifics, especially in toad-naïve populations. Small lizards were more cautious in investigating novel prey (more tongue flicks and bites prior to ingestion) and swallowed the item more slowly. These traits may allow smaller lizards to detect and avoid toad toxins. Seventy percent of monitors from toad-naïve populations readily consumed dead cane toads (with parotoid glands removed) and 85 % consumed frogs. In contrast, no conspecifics from toad-exposed populations consumed toads whereas 40 % ate frogs. Following a single meal of toxic toad (typically eliciting illness), all monitors refused toads but 40 % continued to eat frogs. Lace monitors thus can rapidly learn taste aversion to cane toads. This behavioral plasticity enables survival of smaller lizards (that approach and process prey more cautiously than their larger relatives), and may explain this species’ recovery in long-term toad-colonized regions of northern Australia.
Activation-induced deaminase (AID) initiates hypermutation of Ig genes in activated B cells by converting C:G into U:G base pairs. G₁-phase variants of uracil base excision repair (BER) and mismatch ...repair (MMR) then deploy translesion polymerases including REV1 and Pol η, which exacerbates mutation. dNTP paucity may contribute to hypermutation, because dNTP levels are reduced in G₁ phase to inhibit viral replication. To derestrict G₁-phase dNTP supply, we CRISPR-inactivated SAMHD1 (which degrades dNTPs) in germinal center B cells. Samhd1 inactivation increased B cell virus susceptibility, increased transition mutations at C:G base pairs, and substantially decreased transversion mutations at A:T and C:G base pairs in both strands. We conclude that SAMHD1’s restriction of dNTP supply enhances AID’s mutagenicity and that the evolution of Ig hypermutation included the repurposing of antiviral mechanisms based on dNTP starvation.
During the late Pleistocene, isolated lineages of hominins exchanged genes thus influencing genomic variation in humans in both the past and present. However, the dynamics of this genetic exchange ...and associated phenotypic consequences through time remain poorly understood. Gene exchange across divergent lineages can result in myriad outcomes arising from these dynamics and the environmental conditions under which it occurs. Here we draw from our collective research across various organisms, illustrating some of the ways in which gene exchange can structure genomic/phenotypic diversity within/among species. We present a range of examples relevant to questions about the evolution of hominins. These examples are not meant to be exhaustive, but rather illustrative of the diverse evolutionary causes/consequences of hybridization, highlighting potential drivers of human evolution in the context of hybridization including: influences on adaptive evolution, climate change, developmental systems, sex-differences in behavior, Haldane's rule and the large X-effect, and transgressive phenotypic variation.
Urban ecosystems and remnant habitat 'islands' therein, provide important strongholds for many wildlife species including those of conservation significance. However, the persistence of these ...habitats can be undermined if their structure and function are too severely disrupted. Urban wetlands, specifically, are usually degraded by a monoculture of invasive vegetation, disrupted hydrology, and chronic-contamination from a suite of anthropogenic pollutants. Top predators—as bioindicators—can be used to assess and monitor the health of these ecosystems. We measured eight health parameters (e.g., parasites, wounds and scars, tail loss and body condition) in a wetland top predator, the western tiger snake, Notechis scutatus occidentalis. For three years, snakes were sampled across four wetlands along an urban gradient. For each site, we used GIS software to measure the area of different landscapes and calculate an urbanisation–landscape score. Previously published research on snake contamination informed our calculations of a metal-pollution index for each site. We used generalised linear mixed models to assess the relationship between all health parameters and site variables. We found the metal-pollution index to have the most significant association with poor body condition. Although parasitism, tail loss and wounds differed among sites, none of these parameters influenced body condition. Additionally, the suite of health parameters suggested differing health status among sites; however, our measure of contemporary landscape urbanisation was never a significant predictor variable. Our results suggest that the health of wetland predators surrounding a rapidly growing city may be offset by higher levels of environmental pollution.
Display omitted
•Tiger snake health parameters differed among urban wetlands.•Urbanisation and metal(loid) pollution were not correlated.•Metal(loid) pollution was the strongest predictor of poor body condition.•Snakes in the most urbanised and polluted wetland had similar poor health profiles.•Poor body condition may translate into reduced population fitness.
Commonly, invaders have different impacts in different places. The spread of cane toads (Rhinella marina: Bufonidae) has been devastating for native fauna in tropical Australia, but the toads' impact ...remains unstudied in temperate‐zone Australia. We surveyed habitat characteristics and fauna in campgrounds along the central eastern coast of Australia, in eight sites that have been colonized by cane toads and another eight that have not. The presence of cane toads was associated with lower faunal abundance and species richness, and a difference in species composition. Populations of three species of large lizards (land mullets Bellatorias major, eastern water dragons Intellagama lesueurii, and lace monitors Varanus varius) and a snake (red‐bellied blacksnake Pseudechis porphyriacus) were lower (by 84 to 100%) in areas with toads. The scarcity of scavenging lace monitors in toad‐invaded areas translated into a 52% decrease in rates of carrion removal (based on camera traps at bait stations) and an increase (by 61%) in numbers of brush turkeys (Alectura lathami). The invasion of cane toads through temperate‐zone Australia appears to have reduced populations of at least four anurophagous predators, facilitated other taxa, and decreased rates of scavenging. Our data identify a paradox: The impacts of cane toads are at least as devastating in southern Australia as in the tropics, yet we know far more about toad invasion in the sparsely populated wilderness areas of tropical Australia than in the densely populated southeastern seaboard.
Our manuscript provides the first robust information about the impact of invasive cane toads on the fauna of temperate‐zone Australia. We show dramatic impacts of the invasive toad on a broad suite of native species and demonstrate that toad invasion disrupts ecological functioning by eliminating the primary scavengers in this system (lace monitors, Varanus varius). Our results highlight how a single invasive species can inflict diverse impacts (including, on a critical function such as carrion removal), and also, show how easily major impacts of an invader can remain undetected even in densely populated areas.
PDF
