Like several other intracellular pathogens, Mycobacterium marinum (Mm) escapes from phagosomes into the host cytosol where it can polymerize actin, leading to motility that promotes spread to neighboring cells. However, only ∼25% of internalized Mm form actin tails, and the fate of the remaining bacteria has been unknown. Here we show that cytosolic access results in a new and intricate host pathogen interaction: host macrophages ubiquitinate Mm, while Mm shed their ubiquitinated cell walls. Phagosomal escape and ubiquitination of Mm occured rapidly, prior to 3.5 hours post infection; at the same time, ubiquitinated Mm cell wall material mixed with host-derived dense membrane networks appeared in close proximity to cytosolic bacteria, suggesting cell wall shedding and association with remnants of the lysed phagosome. At 24 hours post-infection, Mm that polymerized actin were not ubiquitinated, whereas ubiquitinated Mm were found within LAMP-1–positive vacuoles resembling lysosomes. Though double membranes were observed which sequestered Mm away from the cytosol, targeting of Mm to the LAMP-1–positive vacuoles was independent of classical autophagy, as demonstrated by absence of LC3 association and by Atg5-independence of their formation. Further, ubiquitination and LAMP-1 association did not occur with mutant avirulent Mm lacking ESX-1 (type VII) secretion, which fail to escape the primary phagosome; apart from its function in phagosome escape, ESX-1 was not directly required for Mm ubiquitination in macrophages or in vitro. These data suggest that virulent Mm follow two distinct paths in the cytosol of infected host cells: bacterial ubiquitination is followed by sequestration into lysosome-like organelles via an autophagy-independent pathway, while cell wall shedding may allow escape from this fate to permit continued residence in the cytosol and formation of actin tails.

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Congenital athymia is an ultra-rare disease characterized by the absence of a functioning thymus. It is associated with several genetic and syndromic disorders including FOXN1 deficiency, 22q11.2 deletion, CHARGE Syndrome (Coloboma, Heart defects, Atresia of the nasal choanae, Retardation of growth and development, Genitourinary anomalies, and Ear anomalies), and Complete DiGeorge Syndrome. Congenital athymia can result from defects in genes that impact thymic organ development such as FOXN1 and PAX1 or from genes that are involved in development of the entire midline region, such as TBX1 within the 22q11.2 region, CHD7, and FOXI3. Patients with congenital athymia have profound immunodeficiency, increased susceptibility to infections, and frequently, autologous graft-versus-host disease (GVHD). Athymic patients often present with absent T cells but normal numbers of B cells and Natural Killer cells (T−B+NK+), similar to a phenotype of severe combined immunodeficiency (SCID); these patients may require additional steps to confirm the diagnosis if no known genetic cause of athymia is identified. However, distinguishing athymia from SCID is crucial, as treatments differ for these conditions. Cultured thymus tissue is being investigated as a treatment for congenital athymia. Here, we review what is known about the epidemiology, underlying etiologies, clinical manifestations, and treatments for congenital athymia.

Maternal and cord measles and rubella antibodies were compared in 15 populations from Brazil, Ecuador, Chile, India, Jordan, Nigeria, South Africa, Taiwan, and the United States. Review of the literature concerning these countries showed that a higher proportion of children 6-12 months of age responded immunologically to measles vaccine in areas with low per capita product than in wealthier populations. The authors show that this difference reflects differences in maternal antibody titer and differences in efficiency of transport of measles immunity across the placenta. No variation in the half-life of passive measles immunity in the infant was found in comparing three geographic areas. When these biologic factors are fully evaluated, it should be possible to predict the response to be expected from vaccination at any particular age without directly testing the vaccine in children below and above generally recommended ages for vaccination. With regard to rubella, high antibody prevalence rates were found in most of the developing countries, as well as in the United States, and these countries are therefore unlikely to encounter widespread problems with congenital rubella. However, Taiwan, and all of four areas of Brazil have prevalence rates which are no higher than those which pertained in the United States prior to establishment of the rubella immunization program. The authors believe that protection of the infants in these countries is a matter of high priority, but that, if approached hastily, it could exacerbate the problem.