Actinomyces species are ubiquitous, commensal, facultatively anaerobic, filamentous Gram-positive bacteria that live in our mouth and intestine but may translocate and invade brain, liver, or pelvis, usually through wounds or in immunosuppressed individuals. Actinomyces’ main virulence/evasion factors are biofilms and (fungus-like) filament branching formation. The genetic etiology for actinomycosis susceptibility is not yet known.
A 15-year-old male from rural Veracruz, born of a non-consanguineous family with five asymptomatic siblings and a personal history of cleft lip and palate. At age 10, he developed a fever, malaise, chronic cough, and abdominal pain. On physical examination, an abdominal mass was found, as well as jaundice, multiple dental cavities, absent teeth, bifid uvula, neck lymphadenopathies, and hepatomegaly palpable 5 cm below the costal margin. Further investigation revealed a 12.5 x 15.5-cm liver tumor, undernutrition with Tanner stage 1, a lung cyst, hepato-cutaneous fistula, empyema, atelectasis, and kidney ectasis.
Laboratory workup reported a normal DHR oxidation, microcytic/hypochromic anemia (10.6 g/dl), leukocytosis (14,500-19,300/mm3 WBC), thrombocytosis (627-413k), and pan-hypergammaglobulinemia (IgG 2230, IgA 674, and IgM 237 mg/dl), with normal serum complement, liver function tests, coagulation assays, C-reactive protein, erythrocyte sedimentation rate, and lymphocyte subsets. Serum autoantibodies were negative, except for slight positivity of anti-phospholipid. The hepatic ultrasound found a vascularized mass of 62 x 45 x 45 mm; a liver biopsy identified fibrosis and chronic inflammation; and the Splendore-Hoeppli reaction, highly suggestive of Actinomyces, also observable in secretion from the fistula.
The patient was treated with penicillin, hydroxychloroquine, and ambulatory antimicrobial prophylaxis. Whole-exome sequencing analysis identified a compound heterozygous genotype: a nonsense variant in exon 8/9 of DNASE1 (c.730C>T, p.Arg244Ter), exceedingly rare (MAF gnomAD 3.58e-5), likely deleterious (CADD Phred 37), and highly conserved across species (GERP++RS 4.5), classified as a VUS; a (trans) heterozygous missense variant affecting the same codon (p.Arg244Gln); and a third heterozygous variant of interest in UNC93B1 (c.439G>A, p.Ala147Thr). Familial segregation analysis and functional validation assays are underway.
Immunity against Actinomyces is not understood. DNASEs are endonucleases that remove extracellular self-DNA. Studies have shown a role for DNASE1 in digesting neutrophil external traps and in limiting the damage caused by staphylococcal infection in mice, by facilitating removal of biofilms.
